This invention relates to a novel series of chemical compounds useful as HIV protease inhibitors and to the use or such compounds as antiviral agents.
Acquired Immune Deficiency Syndrome (AIDS) is a relatively newly recognized disease or condition. AIDS causes a gradual breakdown of the body""s immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980""s, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotromic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.
HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell""s chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body""s immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Karposis sarcoma, and cancer of the lymph system.
Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (AZT) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus.
Retroviral replication routinely features post-translational processing of polyproteins. This processing is accomplished by virally encoded HIV protease enzyme. This yields mature polypeptides that will subsequently aid in the formation and function of infectious virus. If this molecular processing is stifled, then the normal production of HIV is terminated. Therefore, inhibitors of HIV protease may function as anti-HIV viral agents.
HIV protease is one of the translated products from the HIV structural protein pol gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thereby rendering the virion replication-competent. As such, inhibition of the HIV protease by potent compounds may prevent proviral integration of infected T-lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit viral proteolytic processing during its late stage. Additionally, the protease inhibitors may have the advantages of being more readily available, longer lived in virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.
In accordance with this invention, there is provided a novel class of chemical compounds that can inhibit and/or block the activity of the HIV protease, which halts the proliferation of HIV virus, pharmaceutical compositions containing these compounds, and the use of the compounds as inhibitors of the HIV protease.
The present invention relates to compounds falling within formula (1) below, and pharmaceutically acceptable salts thereof, that inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2). These compounds are useful in the treatment of infection by HIV and the treatment of acquired immune deficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and the pharmaceutical compositions of the present invention can be used alone or in combination with other antivirals, immunomodulators, antibiotics or vaccines. Compounds of the present invention can also be used as prodrugs. Methods of treating AIDS, methods of treating HIV infection and methods of inhibiting HIV protease are disclosed.
The compounds of the present invention are of the formula (1): 
wherein:
Q1 and Q2 are independently selected from hydrogen and substituted and unsubstituted alkyl and aryl, and Q1 and Q2 may for a ring with G,
Q3 is selected from mercapto and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle, and aryl,
Q4-Q8 are independently selected from hydrogen, hydroxyl, mercapto, nitro, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, acyl, sulfinyl, sulfonyl, amino, alkyl, cycloalkyl, saturated and partially saturated heterocycle and aryl, and further wherein any one of Q4-Q8 may be a member of a spiro ring and any two of Q4-Q8 may together be members of a ring,
Y and G are independently selected from oxygen, xe2x80x94NH, xe2x80x94N-alkyl, sulfur, selenium, and two hydrogen atoms,
D is carbon or nitrogen,
E is carbon or nitrogen,
Q9 is selected from hydrogen, halogen, hydroxyl, mercapto, and substituted and unsubstituted alkoxyl, aryloxyl, thioether, amino, alkyl, and aryl, wherein Q9 may form part of a ring,
A is a carbocycle or heterocycle, which is optionally further substituted,
and B is a carbocycle or heterocycle, which is optionally further substituted,
or a pharmaceutically acceptable salt thereof.
The invention also relates to compounds of formula (1), wherein all variables are the same as those defined above for formula (1) with the exception of D, which is carbon or nitrogen, and is singly bonded to each of the adjacent ring atoms.
The invention more particularly relates to preferred compounds of formula (1) wherein:
at least one of Q1 and Q2 is substituted or unsubstituted alkyl and the other is as defined above,
Q3 is selected from thioether and aryl,
Q4-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted acyl, alkoxyl, amino and alkyl, and further wherein any one or more of Q4-Q3 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon or nitrogen,
Q9 is hydrogen,
A is a carbocycle or heterocycle that is an aromatic or partially saturated, 5-7 membered mono-ring, which is optionally further substituted,
and B is a heterocycle that is a saturated or partially saturated, 8-12 membered poly-ring, which is optionally further substituted,
or a pharmaceutically acceptable salt thereof.
The invention even more particularly relates to compounds of the formula (1) wherein:
one of Q1 and Q2 is substituted or unsubstituted alkyl, preferably t-butyl, and the other is hydrogen,
Q3 is selected from thioaryl and aryl, preferably thiophenyl and phenyl,
Q4 is alkyl, preferably methyl,
Q5 is hydroxyl or xe2x80x94Oxe2x80x94J, wherein J is a hydrolyzable group, or substituted or unsubstituted alkoxyl or amino,
Q6-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, acyl, amino and alkyl, and further wherein any one or more of Q6-Q8 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon,
Q9 is hydrogen,
A is a carbocycle that is an aromatic, 5-6 membered monocyclic ring, preferably phenyl, which is optionally further substituted,
and B is a heterocycle that is a saturated, 6-14 membered monocyclic or polycyclic ring, which is optionally further substituted, preferably of the formula: 
wherein M1 and M2 are independently selected from hydrogen, mercapto, hydroxyl, and substituted and unsubstituted thioether, alkyl, alkoxyl, aryloxyl, amino, five membered heterocycle and carbocycle, sulfinyl, sulfonyl, and acyl, and wherein M1 and M2 optionally form a ring having up to 10 members, wherein preferably M1 and M2 independently have from zero to eight non-hydrogen atoms;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of the formula (1) include those wherein:
one of Q1 and Q2 is tertiary alkyl, preferably t-butyl, and the other is hydrogen,
Q3 is thiophenyl, phenyl, naphthyl, or thionaphthyl,
Q4 is methyl,
Q5 is hydroxyl, amino, or xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group,
Q6-Q8 are independently selected from hydrogen, hydroxyl, halogen, xe2x80x94Oxe2x80x94J, wherein J is a substituted or unsubstituted hydrolyzable group, and substituted and unsubstituted alkoxyl, acyl, amino and alkyl, and further wherein any one or more of Q6-Q8 may form part of a ring,
Y and G are each oxygen,
D is nitrogen,
E is carbon,
Q9 is hydrogen,
A is phenyl, which is optionally further substituted,
and B is a heterocycle that is a saturated, 9-10 membered bi-ring, preferably decahydroisoquinolinyl or octahydro-thieno[3,2-c]pyridinyl,
or a pharmaceutically acceptable salt thereof.
According to certain embodiments, the portion of formula (1): 
is designated as Z or Z1 and/or the portion of formula (1): 
is designated as X or X1.
According to certain of those embodiments, the compounds have formula 1(A): 
wherein:
Z is a group having the structure: 
where:
a is 1, 2, 3, 4, or 5;
b is 1, or 2;
c is 1, or 2;
d is 1, 2, 3, or 4;
each R2 is independently hydrogen, hydroxy, thiol, halo, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, nitro, carboxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, C1-C6 alkylthio (C1-C6)alkyl, C1-C4 alkoxycarbonyl, carbamoyl, Nxe2x80x94(C1-C4)alkylcarbamoyl, C1-C4 alkylsulfonyl, N,N-di(C1-C4)alkylcarbamoyl, or C1-C4 alkylsulfonylamino;
A1 and A2 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R8)xe2x80x94;
A3 and A4 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
A5 and A6 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R9)xe2x80x94;
A7 and A8 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
R8 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
R1 is aryl, or xe2x80x94S-aryl;
X is a group having the structure: 
where:
R is hydrogen, C1-C4 alkyl, or xe2x80x94CH2-pyridyl;
R3 is a group having the structure:
1) xe2x80x94C(O)xe2x80x94NR4R4, 
p is 4 or 5;
R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy (C1-C4) alkyl; and
R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy (C1-C4)alkyl; with the provisos that:
(1) one of A1 and A2 must be xe2x80x94N(R8)xe2x80x94;
(2) A1 and A2 cannot both be xe2x80x94N(R8)xe2x80x94;
(3) A3 and A4 cannot both be xe2x80x94Nxe2x80x94;
(4) one of A5 and A6 must be xe2x80x94N(R9);
(5) A5 and A6 cannot both be xe2x80x94N(R9)xe2x80x94;
(6) A7 and A8 cannot both be xe2x80x94Nxe2x80x94;
or a pharmaceutically acceptable salt thereof.
Also, according to certain of those embodiments, the compounds have the formula 1(B): 
wherein:
R1 is aryl, or xe2x80x94S-aryl;
X1 is a group having the formula: 
R2 is hydrogen, halo, or C1-C4 alkyl;
R3 is a group having the structure:
1) xe2x80x94C(O)xe2x80x94NR4R4, 
p is 4 or 5;
R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy (C1-C4) alkyl; and
R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy(C1-C4)alkyl;
z1 is a group having the structure: 
where:
a is 1, 2, 3, 4, or 5;
b is 1, or 2;
c is 1, or 2;
d is 1, 2, 3, or 4;
each R7 is independently hydrogen, hydroxy, thiol, halo, amino, C1-C4 alkylamino, di(C1-C4)alkylamino, nitro, carboxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, halo(C1-C4)alkyl, hydroxy (C1-C4)alkyl, C1-C4 alkylthio(C1-C4)alkyl, C1-C4 alkoxycarbonyl, carbamoyl, Nxe2x80x94(C1-C4)alkylcarbamoyl, C1-C4 alkylsulfonyl, N,N-di(C1-C4)alkylcarbamoyl, or C1-C4 alkylsulfonylamino;
A1 and A2 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R8)xe2x80x94;
A3 and A4 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
A5 and A6 are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R9)xe2x80x94;
A7 and A8 are independently xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
R8 is hydrogen or C1-C4 alkyl;
R9 is hydrogen or C1-C4 alkyl;
T2 is hydrogen, or C1-C4 alkyl;
with the provisos that:
(1) one of A1 and A2 must be xe2x80x94N(R8)xe2x80x94;
(2) A1 and A2 cannot both be xe2x80x94N(R8)xe2x80x94;
(3) A3 and A4 cannot both be xe2x80x94Nxe2x80x94;
(4) one of A5 and A6 must be xe2x80x94N(R9)xe2x80x94;
(5) A5 and A6 cannot both be xe2x80x94N(R9)xe2x80x94;
(6) A7 and A8 cannot both be xe2x80x94Nxe2x80x94;
or a pharmaceutically acceptable salt thereof.
Preferred species of the formula (1) are: [3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide and its pharmaceutically acceptable salts, especially methanesulfonic acid salt, and its prodrug analogs, wherein the 3xe2x80x3 hydroxy is converted to xe2x80x94Oxe2x80x94J, as defined above, especially the dihydrogen phosphate hydrochloride salt; and [6S-(6R*,3aS*,7aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]-octahydro-thieno[3,2-c]pyridine-6-N-t-butylcaboxamide and its pharmaceutically acceptable salts, especially methanesulfonic acid salt, and its prodrug analogs, wherein the 3xe2x80x3 hydroxy is converted to xe2x80x94Oxe2x80x94J, as defined above.
The present invention further provides pharmaceutical formulations comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, such as a diluent or excipient.
The present invention further provides a method of treating AIDS comprising administering to a host or patient, such as a primate, an effective amount of a compound of the present invention.
The present invention further provides a method of inhibiting HIV replication comprising administering to an HIV infected cell, a cell susceptible to HIV infection or a host or patient, such as a primate, an effective amount of a compound of the present invention.
The present invention provides new compounds falling within formula (1), as described above, that are useful for treating HIV infection and/or AIDS.
Compounds of the formula (1) may be prodrugs. For example, compounds wherein at least one of Q4-Q8 is xe2x80x94Oxe2x80x94J, as defined above, may be used as prodrugs, which can serve to improve the pharmaceutical properties of the compounds, such as pharmacokinetic properties, for example, improved bioavailability or solubility. The preparation of the prodrugs may be carried out by reacting a compound of the formula (1), wherein at least one of Q4-Q8 is xe2x80x94Oxe2x80x94H, with, for example, an activated amino acyl, phosphoryl or hemisuccinyl derivative.
All temperatures stated herein are in degrees Celsius (xc2x0 C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
The term xe2x80x9calkylxe2x80x9d as used herein refers to straight or branched chain groups, preferably, having one to eight, more preferably having one to six, and most preferably having from one to four carbon atoms. The term xe2x80x9cC1-C6 alkylxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms. Exemplary C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkylxe2x80x9d.
The term xe2x80x9ccycloalkylxe2x80x9d represents a saturated or partially saturated, mono or poly-carbocylic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. An exemplary cycloalkyl is a C5-C7 cycloalkyl, which is a saturated hydrocarbon ring structure containing from five to seven carbon atoms.
The term xe2x80x9calkoxylxe2x80x9d represents xe2x80x94O-alkyl. An example of an alkoxyl is a C1-C6 alkoxyl, which represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Exemplary C1-C6 alkoxyl groups include methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, t-butoxyl, pentoxyl, hexoxyl, and the like. C1-C6 alkoxyl includes within its definition a C1-C4 alkoxyl.
The term xe2x80x9carylxe2x80x9d as used herein refers to a carbocyclic or heterocyclic, aromatic, 5-14 membered monocyclic or polycyclic ring. Exemplary aryls include phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.
The term xe2x80x9caryloxylxe2x80x9d represents xe2x80x94O-aryl.
The term xe2x80x9chydrolyzable groupxe2x80x9d is a group, which when bonded to an oxygen, forms an ester, which can be hydrolyzed in vivo to a hydroxyl group. Exemplary hydrolyzable groups, which are optionally substituted, include acyl function, sulfonate function and phosphate function. For example, such hydrolyzable groups include blocked or unblocked amino acid residue, a hemisuccinate residue, and a nicotinate residue.
The term xe2x80x9chalogenxe2x80x9d represents chlorine, fluorine, bromine or iodine. The term xe2x80x9chaloxe2x80x9d represents chloro, fluoro, bromo or iodo.
The term, xe2x80x9ccarbocyclexe2x80x9d represents an aromatic or a saturated or a partially saturated 5-14 membered monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring members are carbon atoms.
The term xe2x80x9cheterocyclexe2x80x9d represents an aromatic or a saturated or a partially saturated, 5-14 membered, monocylic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and wherein any nitrogen and sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any suitable heteroatom or carbon atom. Examples of such heterocycles include decahydroisoquinolinyl, octahydro-thieno[3,2-c]pyridinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, isobenzofuranyl, furazanyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thianthrenyl, triazinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, chromenyl, xanthenyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thiamorpholinyl, thiamorzholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, phenoxathienyl, indolizinyl, isoindolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, tetrahydouinolinyl, cinnolinyl, pteridinyl, carbazolyl, betacarbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.
The term xe2x80x9cthioetherxe2x80x9d includes S-aryl, such as phenylthio and naphthylthio; S-heterocycle where the heterocycle is saturated or partially saturated; Sxe2x80x94(C1-C7)cycloalkyl; and S-alkyl, such as C1-C6 alkylthio. In the thioether, the -aryl, the -heterocycle, the -cycloalkyl and the -alkyl can optionally be substituted. An example of a thioether is xe2x80x9cC1-C6 alkylthioxe2x80x9d, which represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Exemplary C1-C6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, t-butylthio, pentylthio, hexylthio, and the like.
The term xe2x80x9cmercaptoxe2x80x9d represents xe2x80x94SH.
The term xe2x80x9caminoxe2x80x9d represents xe2x80x94NL1L2, wherein L1 and L2 are preferably independently selected from oxygen, carbocycle, heterocycle, alkyl, sulfonyl and hydrogen; or NC(O)L3, wherein L3 is preferably alkyl, alkoxyl, hydrogen or xe2x80x94NL1L2. The aryl, alkyl and alkoxyl groups can optionally be substituted. An example of an amino is C1-C4 alkylamino, which represents a straight or branched alkyl chain having from one to four carbon atoms attached to an amino group. Exemplary C1-C4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, and the like. Another example of an amino is di(C1-C4)alkylamino, which represents two straight or branched alkyl chains, each having from one to four carbon atoms attached to a common amino group. Exemplary di(C1-C4)alkylamino groups include dimethylamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino, and the like. An example of an amino is C1-C4 alkylsulfonylamino, which has a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfonylamino moiety. Exemplary C1-C4 alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino, t-butylsulfonylamino, and the like.
The term xe2x80x9cacylxe2x80x9d, represents L6C(O)L4, wherein L6 is a single bond, xe2x80x94O or xe2x80x94N, and further wherein L4 is preferably alkyl, amino, hydroxyl, alkoxyl or hydrogen. The alkyl and alkoxyl groups can optionally be substituted. An exemplary acyl is a C1-C4 alkoxycarbonyl, which is a straight or branched alkoxyl chain having from one to four carbon atoms attached to a carbonyl moiety. Exemplary C1-C4 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and the like. Another exemplary acyl is a carboxy wherein L6 is a single bond and L4 is alkoxyl, hydrogen, or hydroxyl. A further exemplary acyl is Nxe2x80x94(C1-C4 )alkylcarbamoyl (L6 is a single bond and L4 is an amino), which is a straight or branched alkyl chain having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary Nxe2x80x94(C1-C4)alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, and N-t-butylcarbamoyl, and the like. Yet another exemplary acyl is N,N-di(C1-C4)alkylcarbamoyl, which has two straight or branched alkyl chains, each having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary N,N-di(C1-C4)alkylcarbamoyl groups include N,N-dimethylcarbamoyl, N,N-ethylmethylcarbamoyl, N,N-methylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl, N,N-butylmethylcarbamoyl, N,N-sec-butylethylcarbamoyl, and the like.
The term xe2x80x9csulfinylxe2x80x9d represents xe2x80x94SO-L5, wherein L5 is preferably alkyl, amino, aryl, cycloalkyl or heterocycle. The alkyl, aryl, cycloalkyl and heterocycle can all optionally be substituted.
The term xe2x80x9csulfonylxe2x80x9d represents xe2x80x94SO2-L5, wherein L5 is preferably alkyl, aryl, cycloalkyl, heterocycle or amino. The alkyl, aryl, cycloalkyl and heterocycle can all optionally be substituted. An example of a sulfonyl is a C1-C4 alkylsulfonyl, which is a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfonyl moiety. Exemplary C1-C4 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl and the like.
As indicated above, many of the groups are optionally substituted. Examples of substituents for alkyl and aryl include mercapto, thioether, nitro (NO2), amino, aryloxyl, halogen, hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl and saturated and partially saturated heterocycles. Examples of substituents for heterocycle and cycloalkyl include those listed above for alkyl and aryl, as well as aryl and alkyl.
Exemplary substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three substituents, independently selected from halo, hydroxy, morpholino(C1-C4)alkoxy carbonyl, pyridyl (C1-C4)alkoxycarbonyl, halo (C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, Nxe2x80x94(C1-C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or a group of the formula xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3 or 4; and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C1-C4 )alkylamino.
Another substituted alkyl is halo(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to our carbon atoms with 1-3 halogen atoms attached to it. Exemplary halo(C1-C4)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.
Another substituted alkyl is hydroxy(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to four carbon atoms with a hydroxy group attached to it. Exemplary hydroxy(C1-C4 )alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl and the like.
Yet another substituted alkyl is C1-C4 alkylthio(C1-C4 )alkyl, which is a straight or branched C1-C4 alkyl group with a C1-C4 alkylthio group attached to it. Exemplary C1-C4 alkylthio(C1-C4)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.
Yet another exemplary substituted alkyl is heterocycle(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with a heterocycle attached to it. Exemplary heterocycle(C1-C4)alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and the like.
Yet another substituted alkyl is aryl(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with an aryl group attached to it. Exemplary aryl(C1-C4)alkyl groups include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.
The heterocycle can, for example, be substituted with 1, 2 or 3 substituents independently selected from halo, halo(C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, Nxe2x80x94(C1-C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or a group having the structure xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3 or 4 and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C1-C4)alkylamino.
Examples of substituted heterocycles include 3-N-t-butyl carboxamide decahydroisoquinolinyl, 6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.
Exemplary heterocyclic ring systems represented by A or B include (1) 5-membered monocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolvl and the like; (2) 6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinly, triazinyl and the like; and (3) polycyclic heterocyclic rings groups, such as decahydroisoquinolinyl, octahydro-thieno [3,2-c] pyridinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, and fully or partially saturated analogs thereof.
A cycloalkyl may be optionally substituted with 1, 2 or 3 substituents independently selected from halo, halo(C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, Nxe2x80x94(C1-C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or a group having the structure xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3 or 4 and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C1-C4)alkylamino. Exemplary substituted cycloalkyl groups include 3-methylcyclopentyl, 6-ethoxycyclohexyl, 5-carboxycyclo-heptyl, 6-chlorocyclohexyl and the like.
Exemplary substituted hydrolyzable groups include N-benzyl glycyl, N-Cbz-L-valyl, and N-methyl nicotinate.
Exemplary compounds of formula (1) include those compounds of formula I in each of the incorporated applications Ser. Nos. 08/137,254, 08/133,696, and 08/133,543 that fall within the scope of formula (1) as defined herein.
The compounds of the present invention have at least two asymmetric centers denoted by an asterisk in the formula (1) below: 
As a consequence of these asymmetric centers, the compounds of the present invention can occur in any of the possible stereoisomeric forms, and can be used in mixtures of stereoisomers, which can be optically active or racemic, or can be used alone as essentially pure stereoisomers, i.e., at least 95% pure. All asymmetric forms, individual stereoisomers and combinations thereof, are within the scope of the present invention.
The individual stereoisomers may be prepared from their respective precursors by the procedures described above, by resolving the racemic mixtures, or by separating the diastereomers. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known in the art. Further details regarding resolutions can be found in Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley and Sons 1981.
Preferably, the compounds of the present invention are substantially pure, i.e, over 50% pure. More preferably, the compounds are at least 75pure. Even more preferably, the compounds are more than 90% pure. Even more preferably, the compounds are at least 95% pure, more preferably, at least 97% pure, and most preferably at least 99% pure.
As mentioned above, the invention includes the pharmaceutically acceptable salts of the compounds defined by formula (1). A compound of this invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d, as used herein, refers to salts of the compounds of the above formula which are substantially nontoxic to living organisms. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. The reactants are generally combined in a mutual solvent such as diethylether or benzene, for acid addition salts, or water or alcohols for base addition salts. The salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods. Such salts are known as acid addition and base addition salts.
Acids that may be employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monchydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycollate, tartrate, methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like.
Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic and organic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute a undesired qualities to the salt as a whole.
Certain compounds are those compounds of formula 1(A) above wherein:
Z is a group having the structure: 
R2 is hydrogen, hydroxy, C1-C4 alkyl, halo, amino, nitro, or trifluoromethyl;
a is 1, 2, or 3;
c is 1; and
R3 is xe2x80x94C(O)NR4R4;
or a pharmaceutically acceptable salt thereof.
Of these compounds, more preferred are those compounds where:
Z is 
R2 is hydrogen, methyl, ethyl, propyl, chloro, fluoro, hydroxy, or amino;
X is 
R is xe2x80x94CH2-pyridyl;
R1 is phenyl or S-phenyl; and
R3 is xe2x80x94C(O)NH(R4);
or a pharmaceutically acceptable salt thereof.
Of these compounds, especially preferred are those compounds where:
Z is 
R2 a is methyl, ethyl, or propyl;
R2b is hydrogen, hydroxy, or amino;
R2c is hydrogen, hydroxy, or amino;
X is 
R3 is xe2x80x94C(O)NH(t-butyl);
or a pharmaceutically acceptable salt thereof.
Certain other preferred compounds are those compounds of formula 1(B) wherein: 
T2 is hydrogen or methyl;
Z1 is a group having the structure: 
R7 is hydrogen, C1-C4 alkyl, halo, nitro, amino, hydroxy;
a is 1, 2, or 3;
c is 1;
or a pharmaceutically acceptable salt thereof.
Of these compounds, more preferred are those compounds where:
Z1 is 
R7 is hydrogen, methyl, ethyl, hydroxy, amino, chloro;
R1 is xe2x80x94S-phenyl, or xe2x80x94S-naphth-2-yl; and
R3 is xe2x80x94C(O)NR4 R4;
or a pharmaceutically acceptable salt thereof.
Of these compounds, especially preferred are those compounds where:
Z1 is 
R7 a is hydrogen, methyl, ethyl, chloro, bromo, or fluoro;
R7b is hydrogen, hydroxy, chloro, or amino;
R7c is hydrogen, hydroxy, or amino;
R3 is xe2x80x94C(O)NH(t-butyl);
or a pharmaceutically acceptable salt thereof.
Preferred compounds are:
2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide: 
2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide methanesulfonic acid salt: 
2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide 3xe2x80x3-dihydrogen phosphate hydrochloride salt: 
2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]octahydro-thieno[3,2-c]pyridine-6-N-t-butylcarboxamide: 
and
2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]-octahydro-thieno[3,2c-]pyridine-6-N-t-butylcarboxamide methanesulfonic acid salt: 
Each of the above five formulae has five assymetric centers and thus defines a compound selected from the group of 32 individual stereoisomers and any mixture of two or more stereoisomers.
Preferred stereisomers of these compounds are:
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl] decahydroisoquinoline-3-N-t-butylcarboxamide: 
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl] decahydroisoquinoline-3-N-t-butylcarboxamide methanesulfonic acid salt: 
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl] decahydroisoquinoline-3-N-t-butylcarboxamide 3xe2x80x3-dihydrogen phosphate hydrochloride salt: 
[6S-(6R*,3aS*,7aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]octahydro-thieno[3,2-c]pyridine-6-N-t-butylcarboxamide: 
and
[6S-(6R*,3aS*,7aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]octahydro-thieno[3,2c-]pyridine-6-N-t-butylcarboxamide methanesulfonic acid salt: 
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2R*)]-2-[2xe2x80x2-hydroxy-3xe2x80x3-phenylmethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-propyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide; 
[2S-(2R*,2xe2x80x2S*,3xe2x80x2S*)]-1-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(3xe2x80x3-hydroxy-2xe2x80x3-methylphenyl)pentyl]-4-pyrid-3xe2x80x3-ylmethyl piperazine-2-N-t-butylcarboxamide; 
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(1xe2x80x3,2xe2x80x3,3xe2x80x3,4xe2x80x3-tetrahydroquinolin-5xe2x80x3-yl)pentyl] decahydroisquinoline-3-N-t-butylcarboxamide; 
[3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2R*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylmethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide; 
[3S-(3R*,4R*,8aR*,2xe2x80x2S*,3xe2x80x2R*)]-2-[2xe2x80x2-hydroxy-3xe2x80x2-phenylmethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-ethyl-3xe2x80x2-hydroxyphenyl)pentyl] decahydroisoquinoline-3-N-t-butylcarboxamide; 
[2Rxe2x80x2-(2xe2x80x2R*,3xe2x80x2S*)]-N-t-butyl-2-[2xe2x80x2-hydroxy-3xe2x80x2-naphth-2-ylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(1xe2x80x3,2xe2x80x3,3xe2x80x3,4xe2x80x3-tetrahydroquinolin -5xe2x80x3-yl)pentyl] benzamide;
[2xe2x80x2R-(2xe2x80x2R*,3xe2x80x2S*)]-N-t-butyl-2-[2xe2x80x2-hydroxy-3xe2x80x2-naphth-2-ylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl] benzamide;
[2xe2x80x2-(2xe2x80x2R*,3xe2x80x2S*)]-N-t-butyl-2-[2xe2x80x2-hydroxy-3xe2x80x2-naphth-2-ylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3,5xe2x80x3-diaminophenyl)pentyl] benzamide;
[2xe2x80x2R-(2xe2x80x2R*,3xe2x80x2S*)]-N-t-butyl-2-[2xe2x80x2-hydroxy-3xe2x80x2-naphth-2-ylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-methyl-3xe2x80x3-hydroxyphenyl)pentyl]-1-naphthylamide; and
(2xe2x80x2R-(2xe2x80x2R*,3,S*)]-N-t-butyl-2-(2xe2x80x2-hydroxy-3xe2x80x2-naphth-2-ylthiomethyl-4xe2x80x2-aza-5xe2x80x2-oxo-5xe2x80x2-(2xe2x80x3-chloro-3xe2x80x3-aminophenyl)pentyl]-1-naphthylamide;
or a pharmaceutically acceptable salt of any of the foregoing most preferred compounds.
The compounds of formula 1 can he prepared according to the following Reaction I.
Reaction I 
where the variables are as defined for formula 1 above.
Reaction I is a standard coupling reaction commonly employed in the synthesis of amides which is carried out by reacting an appropriately substituted amine of formula IA, with an appropriately substituted carboxylic acid reactant of formula IB, in an aprotic solvent or mixture of solvents. The reaction is carried out in the presence or absence of a promoting agent, preferably in the presence of a promoting agent, and in the presence of a coupling reagent. Typical aprotic solvents for this reaction are tetrahydrofuran and dimethylformamide, or a mixture of such solvents. The reaction is carried out at a temperature from about xe2x88x9230xc2x0 C. to about 25xc2x0 C. The amine reactant is generally employed in equimolar proportions relative to the carboxylic acid reactant, in the presence of an equimolar quantity to a slight excess of the coupling reagent. Typical coupling reagents include the carbodiimides such as dicyclohexylcarbodiimide (DCC) and N,Nxe2x80x2-diethylcarbodiimide; the imidazoles such as carbonyldiimidazole; as well as reagents such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). A preferred coupling reagent for this reaction is DCC. A promoting agent is preferably included for this reaction; a preferred promoting agent is hydroxybenzotriazole hydrate (HOBTxc2x7H2O).
Once the reaction is complete, the compound may be isolated, if desired, by procedures known in the art, for example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The compound may be further purified, if desired, by common techniques such as crystallization or chromatography over solid supports such as silica gel or alumina.
The starting compounds of formula IA may be prepared according to the procedures shown in Reaction Scheme A. 
where:
VA is an amino-protecting group;
B, D, G, Q1, Q2, Q3, and Q9 are defined the same as they are defined above for formula (1); and
ZZ is halo.
Reaction Scheme A, above, is accomplished by carrying out reactions 1-7 in sequential order. Once a reaction is complete, the intermediate compound may be isolated, if desired, by procedures known in the art, for example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The intermediate compound may be further purified, if desired, by common techniques such as crystallization or chromatography over solid supports such as silica gel or alumina, before carrying out the next step of the reaction scheme.
Reaction A.1 is carried out by converting an amino-protected carboxylic acid reactant having the structure: 
to the corresponding mixed anhydride under conditions known in the art. For example, the amino-protected carboxylic acid reactant may be reacted with a C1-C6 alkylchloroformate, such as isobutylchloroformate preferably in the presence of an acid scavenger. Preferred acid scavengers are the trialkylamines, preferably triethylamine. The reaction is typically carried out in an aprotic solvent such as ethyl acetate. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. The resulting mixed anhydride reactant is preferably used in Reaction A.2 without further isolation or purification.
Reaction A.2 is accomplished in two steps. First, a solution of sodium hydroxide, covered with a layer of an ether solvent, preferably diethyl ether, is reacted with a large excess of N-methyl-N-nitro-N-nitrosoguanidine to form a diazomethane reactant. The sodium hydroxide is preferably used as an aqueous solution having about four to six mol/liter of sodium hydroxide. Once this reaction is substantially complete, the organic layer is dried over a dessicant such as potassium hydroxide. This solution is then reacted with the mixed anhydride from Reaction A.1, above, to form the corresponding aldhadiazo carbonyl compound. The diazomethane reactant is preferably used in this reaction without isolation or purification. The reaction is typically carried out at a temperature of from about xe2x88x9250xc2x0 C. to about xe2x88x9210xc2x0 C., preferably about xe2x88x9220xc2x0 C.
In Reaction A.3, the alpha-diazo carbonyl compound prepared in Reaction A.2 is reacted with an acid of the formula H-ZZ where ZZ is halo, in an aprotic solvent such as diethylether to form an alpha-halo carbonyl compound. A preferred acid reactant is hydrochloric acid which provides the corresponding alpha-chloro carbonyl compound. The reaction is typically carried out at a temperature from about xe2x88x9230xc2x0 C. to about 0xc2x0 C. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. The acid reactant is typically added in the form of an anhydrous gas in small increments until the reaction appears substantially complete. The reaction can be monitored by thin layer chromatography.
In Reaction A.4, the carbonyl moiety on the compound prepared in Reaction A.3 is reduced using standard conditions known in the art to form the corresponding alpha-chloro hydroxy compound. For example, the compound prepared in Reaction A.3 is combined with a reducing agent in a mixture of solvents. Typical reducing agents include sodium borohydride, lithium borohydride, zinc borohydride, diisobutylaluminum hydride, and sodium bis(2-methoxy-ethoxy) aluminum hydride. A preferred reducing agent is sodium borohydride. Typical solvent mixtures include a protic and aprotic mixture such as tetrahydrofuran/water. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction, and the reactants are sufficiently solubilized to effect the desired reaction. The reaction is typically carried out at a temperature from about xe2x88x9210xc2x0 C., preferably about 0xc2x0 C.
In Reaction A.5, the alpha-chloro hydroxy compound prepared in Reaction A.4 is treated with a strong base to form the corresponding epoxide (which is used above in Reaction II.5) under standard conditions known in the art. For example, the alpha-chloro hydroxy compound may be reacted with a potassium hydroxide/ethanol mixture in an alcoholic solvent such as ethanol. The reaction is typically carried out at a temperature from about 0xc2x0 C. to about the reflux temperature of the solvent. Preferably the reaction is carried out at room temperature.
In Reaction A.6, the epoxide prepared in Reaction A.5 is reacted with a heterocyclic reactant: 
in an alcoholic solvent at a temperature of from about 20xc2x0 C. to 100xc2x0 C. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. Typical solvents for this reaction include the alcohols, preferably isopropanol or ethanol. The reaction is preferably carried out at a temperature of about 80xc2x0 C.
Reaction A.7 is a standard amino deprotection reaction using procedures and methods known in the art to afford the corresponding amine which is used in Reaction I, above. This amine may be reacted without purification, but it is preferably purified first.
The compounds of formula IA, where Q3 is xe2x80x94S-aryl, are prepared by first reacting amino-protected serine with triphenylphosphine and diethylazodicarboxylate (DEAD) in an aprotic solvent at a temperature of from about xe2x88x9280xc2x0 C. to 0xc2x0 C. to form the corresponding beta-lactone. The reaction is typically carried out in an ether, such as tetrahydrofuran at a temperature of from about xe2x88x9280xc2x0 C. to xe2x88x9250xc2x0 C. Next, the lactone ring is opened to provide a compound having the structure: 
by reacting the lactone with an appropriately substituted thioanion having the structure, xe2x80x94Sxe2x80x94aryl. The thioanion compound is preferably formed by reacting the corresponding thiol with a strong base, such as sodium hydride or potassium hydride. This reaction is typically carried out in an aprotic solvent at a temperature from about 0xc2x0 C. to about 40xc2x0 C. and under an inert atmosphere, such as nitrogen. Typical solvents for this reaction include ethers, preferably tetrahydrofuran.
Alternatively, the compounds of formula IA, where Q7 is xe2x80x94Sxe2x80x94aryl, may be prepared using the procedures detailed in Photaki, JACS, 85, 1123 (1963), and Sasaki, N. A. et al, Tetrahedron Letters, 28, 6069 (1987). For example, the compounds may be prepared by reacting doubly protected serine (carboxy-protected and amino-protected) with toluenesulfonyl chloride in the presence of dimethylaminopyridine (DMAP) and an acid scavenger such as pyridine in an aprotic solvent such as methylene chloride to form the corresponding toluenesulfonate which may then be reacted with an appropriately substituted thioanion having the structure, xe2x80x94Sxe2x80x94aryl. The thioanion compound is preferably formed by reacting the corresponding thiol with a strong base as described above. The carboxy-protecting group may be removed from the resulting doubly protected arylthioalanine using conditions known in the art.
The heterocyclic reactants of the formula 
used in Reaction A.6, may be prepared using procedures and methods known in the art. For example, the heterocyclic reactants were typically prepared from the corresponding amino-protected amino acids by acid activation followed by treatment with an alkylamine. This reaction is typically carried out in the presence of an acid scavenger, such as N-methylmorpholine. Removal of the amino-protecting group using standard chemical deprotecting techniques then provides the desired heterocyclic reactants. Specifically, the [3S-(3R*,4aR*,8aR*)]-decahydroisoquinoline-3-N-t-butylcarboxamide was prepared using 2S-1,2,3,4-tetrahydro-3-isocuinolinecarboxylic acid by the following procedure:
1) amino-protection (t-Boc);
2) acid activation/reaction with t-butylamine;
3) catalytic hydrogenation;
4) amino-deprotection.
The piperazine reactants may be prepared by converting an appropriately substituted pyrazine compound to the corresponding piperazine compound using procedures known in the art, preferably using catalytic hydrogenation. For example, the hydrogenation may be accomplished by combining the pyrazine reactant with a catalyst under a hydrogen atmosphere in an aprotic solvent at a temperature from about 0xc2x0 C. to about 60xc2x0 C. Suitable catalysts include palladium-on-carbon, platinum metal, platinum oxide and the like. A preferred catalyst is platinum oxide. Typical solvents for this reaction include tetrahydrofuran, dimethylformamide or a mixture of tetrahydrofuran and dimethylformamide.
The nitrogen atom on the resultant piperazine reactant may be alkylated using procedures known in the art. For example, the piperazine reactant may be reacted with a halo(C1-C4)alkyl, or halomethylpyridine, such as methyl iodide or chloromethylpyridine. Preferred halo substituents include chloro, bromo and iodo. The reaction is carried out at temperatures of from about 0xc2x0 C. to 60xc2x0 C. in a mutually inert solvent and in the presence of an acid scavenger. A preferred acid scavenger is potassium carbonate. Typical solvents include a mixture of a protic and aprotic solvents such as acetonitrile and water. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
Alternatively, the alkylated piperazine reactant may be prepared using reductive amination. For example, the piperazine reactant prepared above may be reacted with an aldehyde (for example, 3-pyridine carboxylic aldehyde, ethanal, propanal) or a ketone in the presence of a reducing agent and an acid. The reaction is typically carried out in an alcoholic solvent such as methanol, ethanol or isopropanol. Typical reducing agents include sodium borohydride, lithium cyanoborohydride, sodium cyanoborohydride, and the like. A preferred reducing agent is sodium cyanoborohydride. Typical acids include any protic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, or acetic acid. A preferred acid is acetic acid.
The intermediate reactant 
can also be prepared that has the formula 2: 
wherein:
V0 and V1 are independently hydrogen, C1-C6 alkyl, or hydroxy (C1-C6) alkyl;
V2 is hydrogen, an amino-protecting group, or a group of the formula: 
V3 is xe2x80x94(CH2)txe2x80x94V3xe2x80x2;
t is 0, 1, 2, 3, or 4;
V3xe2x80x2 is aryl, xe2x80x94Oxe2x80x94aryl, or xe2x80x94Sxe2x80x94aryl;
V4 is hydrogen or an amino-protecting group; f, h and j are each independently 0, 1 or 2; g and i are each independently 0 or 1;
V5 is xe2x80x94CH2xe2x80x94, xe2x80x94CHV5xe2x80x2xe2x80x94, or xe2x80x94CV5xe2x80x2V5xe2x80x2xe2x80x94;
V6 is xe2x80x94CH2xe2x80x94, CHV6xe2x80x2, xe2x80x94CV6xe2x80x2V6xe2x80x2xe2x80x94;
V7 is xe2x80x94CH2xe2x80x94, xe2x80x94CHV7xe2x80x2, or xe2x80x94CV7xe2x80x2V7xe2x80x2xe2x80x94;
each of V5xe2x80x2, V6xe2x80x2, and V7xe2x80x2 is independently selected from the group consisting of halo, hydroxy, C1-C6 alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, or cyano;
T and W are independently xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94(V9)xe2x80x94; and
V9 is C1-C6 alkyl, aryl(C1-C6)alkyl, aryl, or acyl;
with the provisos that:
g and i cannot both be 0;
the sum of f, g, h, i and j must be 2, 3, 4, or 5;
if V5, is xe2x80x94CV5xe2x80x2V5xe2x80x2xe2x80x94, then V6 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV6xe2x80x2xe2x80x94; and V7 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV7xe2x80x2xe2x80x94;
if V6 is xe2x80x94CV6xe2x80x2V6xe2x80x2xe2x80x94, then V5 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV5xe2x80x2xe2x80x94; and V7 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV7xe2x80x2xe2x80x94;
if V7 is xe2x80x94CV7xe2x80x2V7xe2x80x2xe2x80x94, then V5 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV5xe2x80x2xe2x80x94; and V6 must be xe2x80x94CH2xe2x80x94 or xe2x80x94CHV6xe2x80x2xe2x80x94;
or a pharmaceutically acceptable salt thereof. 
wherein V4, V3, Vo, V1, V5, T, V6, W, V7, f, g, h, i, j, are defined above for formula 2;
VA is an amino-protecting group; and
U on the bicyclic ring in reaction 1-3 above represents the presence of double bonds between, for example, Vf and Vh, Vf and Vf, or Vj and Vh and the like, where b, c, or d is O, respectively.
Reaction Scheme II, above, is accomplished by carrying out reactions 1-3 (or 1-5) in sequential order. Once a reaction is complete, the intermediate compound may be isolated, if desired, by procedures known in the art, for example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The intermediate compound may be further purified, if desired, by common techniques such as crystallization or chromatography over solid supports such as silica gel or alumina, before carrying out the next step of the reaction scheme.
Reaction II.1 is typically carried out by activating the carboxylic acid moiety using, for example, DCC or a mixed anhydride such as isobutyl, followed by reaction with a primary or secondary amine having the formula NV0V1 where V0 and V1 are as defined above for formula (2). The reaction is typically carried out in a nonpolar aprotic solvent or mixture of solvents in the presence or absence of an acid scavenger at a temperature of from about xe2x88x9220xc2x0 C. to about 25xc2x0 C. to afford the corresponding amide. Suitable solvents for this reaction include ethers and chlorinated hydrocarbons, preferably diethyl ether, chloroform, or methylene chloride. Preferably, this reaction is carried out in the presence of an acid scavenger such as a tertiary amine, preferably triethylamine. The amide afforded by this reaction may be isolated or further reacted as shown in Reaction II.2.
Reaction II.2 is typically carried out by reacting the compound obtained from Reaction II.1 using the procedures detailed in Comprehensive Organic Synthesis, xe2x80x9cHeteroatom Manipulationxe2x80x9d, Barry M. Trost, ed., volume 6, pages 736-746, (1991). In general, an appropriately substituted monocyclic ring is reacted with an aldehyde, such as formaldehyde or trichloroacetaldehyde, in the presence of an acid. The acid may be used as a solvent. Typical acids include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like. A co-solvent may optionally be added to the reaction mixture. The co-solvent choice is not critical so long as the co-solvent employee is inert to the ongoing reaction, and the reactants are sufficiently solubilized to effect the desired reaction. Typical solvents for this reaction include halogenated solvents such as methylene chloride, trichloroethane, carbontetrachloride, and the lake. Alternatively, the aldehyde may be produced in situ using for example, dimethoxymethane and a suitable acid.
In reaction II.3, the compound isolated from reaction II.2 is reduced to provide a saturated heterocyclic compound as depicted above. Catalytic hydrogenation is a preferred method of reduction. Typical catalysts include palladium catalysts, rhodium catalysts (for example rhodium on aluminum) and rhenium catalysts. Preferred catalysts include palladium-on-carbon. Suitable solvents for this reaction include the C1-C4 alcohols, tetrahydrofuran, acetic acid in alcohol, ethyl acetate and the like. A preferred solvent is ethanol. The reaction is typically carried out under an atmosphere of hydrogen from about 1000 to about 4000 psi at a temperature of from about 25xc2x0 C. to about 150xc2x0 C. Preferably, the reaction is carried out under an atmosphere of hydrogen from about 2000 to about 3000 psi at a temperature of from about 50xc2x0 C. to 100xc2x0 C. The catalyst is generally employed in a amount ranging from about equimolar proportions to about a twelve-fold excess (by weight) of the reactant, preferably in about a six- to ten-fold excess (by weight) of the catalyst relative to the substrate.
Reactions II.4 and II.5 may be used to prepare compounds of formula (3) which correspond to compounds of formula (2) where
V2 is 
xe2x80x83and
V3 and V4 are as defined above for formula (2), including their definitions or V3 and t.
Reaction II.4 is a standard amino deprotection reaction using procedures and methods known in the art to afford the corresponding amine which is then used in Reaction II.5. Chemical deprotection procedures are preferred. For example, the compound isolated from II.3 may be deprotected using trimethylsilyliodide (TMSI) in an aprotic solvent or mixture of solvents at a temperature of from about 10xc2x0 C. to 60xc2x0 C., preferably at a temperature of from about 20xc2x0 C. to 40xc2x0 C. Typical solvents include mechylene chloride, acetonitrile trichloroethane, and the like.
In Reaction II.5, the epoxide prepared in Reaction A.5, above, in-which Q3 of Reaction A.5 is by V3 is reacted with the compound isolated from Reaction II.4 in an alcoholic solvent at a temperature of from about 20xc2x0 C. to 100xc2x0 C. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction, and the reactions are sufficiently solubilized to effect the desired reaction. Typical solvents for this reaction include the alcohols, preferably isopropanol or ethanol. The reaction is preferably carried out at a temperature of about 80xc2x0 C.
The compound isolated from reaction II.5 may optionally be deprotected to provide a compound of formula (3) where VA is hydrogen.
The epoxide used in Reaction II.5 may be synthesized using Reaction Scheme A above.
The carboxylic acid reactant of formula (IB) 
used in Reaction Scheme I, to the extent not commercially available, can be prepared using known procedures. More particularly, this reactant may be prepared by further substitution and/or oxidation of a commercially available aryl or heterocyclic compound. For example, aryl or heterocyclic compounds of the formula 
may be oxidized using procedures known in the art. Specifically, the compound of the formula 
may be reacted with an oxidizing agent such as selenium dioxide or potassium permanganate at temperatures of from about 0xc2x0 C. to 200xc2x0 C. in a mutually inert solvent, such as water or diphenylether.
A second method for preparing compounds of the formula (IB) involves protecting an appropriately substituted carboxylated aryl or heterocyclic with a carboxy-protecting group, and then further substituting the aryl or heterocyclic group using procedures known in the art. The carboxy-protecting group may then be removed using procedures known in the art to provide the desired carboxylic acid reactant of formula (IB).
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound. Examples of such carboxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxbenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2xe2x80x2,4,4xe2x80x2-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxy-trityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, b-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. A preferred method of protecting the carboxy group involves converting the carboxy moiety to an amide moiety and then hydrolyzing the amide back to provide the desired carboxy substituent. Further examples of these groups are found in E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
A preferred procedure for protecting the carboxy moiety involves the acid activation of the carboxy moiety, followed by the formation of an amide. For example, the carboxy moiety may be converted to an acyl halide, acyl anhydride, acyl imidazole and the like, preferably in the presence of an acid scavenger to form an activated carboxy moiety. A commercially available acid chloride is typically employed, obviating the need for further acid activation. Preferred acid scavengers are the trialkylamines, preferably triethylamine. The reaction is typically carried out in an aprotic solvent such as diethylether, methylene chloride or the like. A preferred solvent is methylene chloride. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. The activated carboxy moiety is then reacted with an amine, R11xe2x80x94NH2, for example aniline, in an aprotic solvent to provide an amide reactant 
which may then be further substituted according to known procedures.
The amide reactant 
may be further substituted by ortho deprotonation of the heterocyclic or aryl group 
to provide the corresponding anion followed by reaction with a variety of reagents such as alkyl halides, or halogenating agents such as bromine. The amide reactant is generally deprotonated twice using two equivalents of a strong base such as n-butyl lithium or sec-butyl lithium relative to the amide reactant, optionally in the presence of a metal coordinating agent such as tetramethylethylenediamine (TMEDA). The reaction is typically carried out in an aprotic solvent, preferably an ether such as diethylether, tetrahydrofuran or the like at a temperature from about xe2x88x9278xc2x0 C. to about 25xc2x0 C.
The resultant compound may then be hydrolyzed using procedures known in the art to provide the desired, substituted carboxylic acid reactant of formula (IB). For example, a suitable hydrolysis involves exposing the amide reactant to a strong mineral acid, organic acid, or a mineral acid/organic mixture at a temperature from about 100xc2x0 C. to about 160xc2x0 C. Typical acids which may be used in this reaction include hydrobromic acid, acetic acid, hydrochloric acid and the like. A sealed tube may optionally be employed to accelerate the reaction rate.
A third method for preparing the substituted carboxylic acid reactant of formula (IB) involves diazotization of an aniline, followed by a quenching of the resultant diazonium salt. Specifically, the amino moiety of the aniline reactant is converted to a diazonium salt by reaction with nitrous acid. Nitrous acid may be produced in situ by treating sodium nitrite with an aqueous solution of a strong acid such as hydrochloric acid, or sulfuric acid. This reaction is typically carried out at or below 5xc2x0 C. The diazonium salt is then quenched by reaction with suitable reagent to provide the desired substituted aromatic system. Representative quenching reagents include water, cyanide, halide, aqueous sulfuric acid, and the like. Typically, the reaction will be heated to facilitate the desired reaction.
There are a variety of reactions that are known in the art which may be used to produce the desired substitutions on the aryl or heterocyclic rings. For example, there are a variety of aromatic electrophilic and nucleophilic substitution reactions outlined in chapters 11 and 13 of March. J., xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d 3rd edition, Wiley, 1985.
In addition, the compounds of the formula (IB) may be prepared by carboxylating an appropriately substituted aryl of heterocyclic compound. The carboxylation may be accomplished using a number of different reagents. For example, the aryl or heterocyclic reagent may be reacted with phosgene, oxalyl chloride, urea hydrochloride, or N,N-diethylcarbamoyl chloride in the presence of Friedel-Crafts catalysts. A variation of this method involves reacting the aryl or heterocyclic reagent with an alkyl thiolchloroformate (RSCOCl), or a carbamoyl chloride (H2NCOCl) to provide an amide and a thiol ester, respectively. The amide and thiol ester may then be hydrolyzed to provide the desired carboxy group. March, at 491.
Examples of Friedel-Crafts catalysts include the Lewis acids, such as aluminum bromide (AlBr3), aluminum chloride (AlCl3), iron (III) chloride (FeCl3), boron trichloride (BCl3), boron trifluoride (BF3), and the like. See also, March, J., xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d 3rd edition, Wiley, 1985; Olah, xe2x80x9cFriedel-Crafts and Related Reactions,xe2x80x9d Interscience, New York, 1963-1965; and Olah, xe2x80x9cFriedel-Crafts Chemistry,xe2x80x9d Wiley, New York, 1973.
Additionally, the quinoline carboxylic acid reactants may be prepared by reacting an appropriately substituted aniline with glycerol using the Skraup reaction disclosed in Bradford, L. et al., J. Chem. Soc., 1947, p 437. For example, 3-amino benzoic acid may be reacted with glycerol in the presence of an oxidizing agent such as m-nitro benzene sulfonic acid or sodium m-nitro benzene sulfonate in a 60-75% aqueous solution of sulfuric acid to provide the desired carboxy-substituted quinoline. The reaction is typically carried out at a temperature from about 35xc2x0 C. to reflux temperature for one to six hours, preferably from about 50xc2x0 C. to reflux temperature for two to four hours.
The resultant reactants may then be reduced or hydrogenated using procedures known in the art. See e.g., March, at 700. A preferred procedure involves catalytic hydrogenation, for example by combining the quinoline carboxylic acid reactant with hydrogen gas in the presence of a catalyst. A preferred catalyst is palladium-on-carbon. Typical solvents suitable for use in this reaction include any organic solvent such as ethyl acetate. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction. The reaction is generally substantially complete after about 1 to 24 hours when conducted at a temperature in the range of from about 25xc2x0 C. to about 100xc2x0 C.
According to other embodiments, the compounds of formula IA, in which Q3 is replaced by R1, can be prepared according to the following Reaction Scheme B. 
where:
Rb is an amino-protecting group; and
R1, and R3 are as defined above for formula 1(B)
Reaction Scheme B, above, is accomplished by carrying out reactions 1-6 in sequential order. Once a reaction is complete, the intermediate compound may be isolated, if desired by Procedures known in the art, for example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The intermediate compound may be further purified, if desired, by common techniques such as crystallization or chromatography over solid supports such as silica gel or alumina, before carrying out the next step of the reaction scheme.
In Reaction B.1, the reaction is typically carried out by activating, that is, converting, a suitably substituted aryl or unsaturated heterocycle carboxylic acid to the corresponding acyl chloride or acyl bromide by reaction with thionyl chloride, thionyl bromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentabromide or phosphorous pentachloride according to procedures and under conditions known in the art. Suitable aryl, heterocycle or unsaturated heterocycle carboxylic acid compounds are commercially available or prepared by standard procedures known in the art.
In Reaction B.2, the acyl chloride or acyl bromide, prepared in Reaction B.1, is reacted with ammonia or a primary or secondary amine having the formula
Hxe2x80x94NR4R4, 
where R4, R5, R6 and p are as defined above for formula 1(B), in a nonpolar aprotic solvent or mixture of solvents in the presence or absence of an acid scavenger to afford the corresponding amide. The reaction is typically carried out at a temperature of from about xe2x88x9220xc2x0 C. to about 25xc2x0 C. Typical solvents for this reaction include ethers and chlorinated hydrocarbons, preferably diethylether, chloroform or methylene chloride. Preferably, this reaction is carried out in the presence of an acid scavenger such as a tertiary amine, preferably triethylamine.
In Reaction B.3, the amide prepared in Reaction B.2, is reacted with a strong base in the presence of a solubilizing agent to afford the corresponding anion which is then reacted in Reaction B.4 with a Weinreb amide to afford a ketone. Reaction B.3 is carried out in an aprotic solvent at a temperature of from about xe2x88x9278xc2x0 C. to about 0xc2x0 C. Typical bases used in Reaction B.3 include lithium amide bases and alkyl lithium bases, preferably C1-C4 alkyl lithium bases and lithium di(C1-C4)alkylamide bases. Typical solubilizing agents or Reaction 3 are tetramethyl(C1-C4)alkylenediamines, preferably tetramethylethylenediamine. Reaction B.4 is carried out in an aprotic solvent at a temperature from about xe2x88x9280xc2x0 C. to about xe2x88x9240xc2x0 C. Typical solvents for Reactions B.3 and B.4 include ethers, preferably tetrahydrofuran. In Reaction B.4, the anion is generally employed in an amount ranging from about equimolar proportions to about a three molar excess of the anion, preferably in about a two molar excess of the anion relative to the Weinreb amide reactant.
In Reaction B.5, the ketone prepared in Reaction B.3, is reduced to the corresponding alcohol using a suitable reducing agent. The reaction is carried out in a protic solvent at a temperature of from about xe2x88x9225xc2x0 C. to about 25xc2x0 C. Typical reducing agents for this reaction include sodium borohydride, lithium borohydride, diisobutylaluminum hydride, and sodium bis(2-methoxyethoxy)aluminum hydride. A preferred reducing agent is sodium borohydride. Typical protic solvents for this reaction include alcohols, preferably ethanol.
Reaction B.6 is a standard amino deprotection reaction using procedures and methods known in the art to afford the corresponding amine which is used in Reaction I above. This amine may be reacted without purification, but it is preferably purified first.
The Weinreb amide used as a reactant in Reaction B.4 is prepared by reacting an amino-protected amino acid with N-methoxy-N-methyl-amine in the presence of a promoting agent, an acid scavenger, and a coupling agent. The reaction is carried out in an aprotic solvent or mixture of solvents at a temperature of from about xe2x88x9225xc2x0 C. to 25xc2x0 C. A preferred promoting agent for this reaction is HOBTxc2x7H2O. Preferred acid scavengers are the tertiary alkylamines, preferably triethylamine or N-methyl-morpholine. A preferred coupling reagent is ethyl dimethylaminopropylcarbodiimide hydrochloride. The Weinreb amide afforded by this reaction is preferably isolated prior to its use in Reaction B.4.
The compounds of formula IA, where R1 replaces Q3 and where R1 is xe2x80x94Sxe2x80x94aryl, are prepared in Scheme B by first reacting amino-protected serine with triphenylphosphine and diethylazodicarboxylate (DEAD) in an aprotic solvent at a temperature of from about xe2x88x9280xc2x0 C. to 0xc2x0 C. to form the corresponding beta-lactone. The reaction is typically carried out in an ether, such as tetrahydrofuran at a temperature of from about xe2x88x9280xc2x0 C. to xe2x88x9250xc2x0 C. Next, the lactone ring is opened to provide a compound having the structure: 
by reacting the lactone with an appropriately substituted thioanion having the structure, xe2x80x94Sxe2x80x94aryl. The thioanion compound is preferably formed by reacting the corresponding thiol with a strong base, such as sodium hydride or potassium hydride. This reaction is typically carried out in an aprotic solvent at a temperature from about 0xc2x0 C. to about 40xc2x0 C. and under an inert atmosphere, such as nitrogen. Typical solvents for this reaction include ethers, preferably tetrahydrofuran. The desired amide reactant is then formed by reacting the resulting carboxylic acid reactant with N-methoxy-N-methyl-amine in the presence of a promoting agent, an acid scavenger and a coupling agent substantially as described above.
Alternatively, the compounds of formula (IA), where R1 replaces Q3 and where R1 is xe2x80x94Sxe2x80x94aryl, may be prepared in Scheme B using the procedures detailed in Photaki, JACS, 85, 1123 (1963), and Sasaki, N. A. et al., Tetrahedron Letters, 28, 6069 (1987). For example, the compounds may be prepared by reacting doubly protected serine (carboxy-protected and amino-protected) with toluenesulfonyl chloride in the presence of dimethylaminopyridine (DMAP) and an acid scavenger such as pyridine in an aprotic solvent such as methylene chloride to form the corresponding toluenesulfonate compound which may then be reacted with an appropriately substituted thioanion having the structure, xe2x80x94Sxe2x80x94aryl. The thioanion compound is preferably formed by reacting the corresponding thiol with a strong base as described above. The carboxy-protecting group may then be removed from the resulting doubly protected arylthioalanine using conditions known in the art.
According to certain embodiments, an intermediate for making compounds of the present invention is prepared as follows. The intermediate has the formula 4: 
wherein:
R1 is aryl, or xe2x80x94Sxe2x80x94aryl;
R10 is hydrogen or an amino-protecting group;
R0 is C1-C4 alkyl or xe2x80x94CH2-pyridyl;
R3is a group having the structure: 
p is 4 or 5;
R4 at each occurrence is independently hydrogen, C1-C6 alkyl or hydroxy(C1-C4)alkyl; and
R5 and R6 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy(C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof; comprising:
(a) reducing a compound of the formula 
xe2x80x83to provide a piperazine compound;
(b) alkylating the piperazine compound to provide a compound of the formula 
xe2x80x83and then
(c) reacting the piperazine compound of step (b) with an epoxide of the formula 
xe2x80x83where Rb is an amino protecting group;
in an alcoholic solvent at a temperature of from about 20xc2x0 C. to 100xc2x0 C. to form a compound of formula II wherein R10 is an amino-protecting group; and
d) optionally removing the amino-protecting group to form a compound of formula 4 wherein R10 is hydrogen.
The following Preparations and Examples illustrate aspects of the invention. These examples are for illustrative purposes and are not intended to limit the scope of the invention.
Abbreviations for the terms melting point, nuclear magnetic resonance spectra, electron impact mass spectra, field desorption mass spectra, fast atom bombardment mass spectra, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chromatography, and thin layer chromatography are, respectively, m.p., NMR, EIMS, MS(FD), MS(FAB), IR, UV, Analysis, HPLC, and TLC. In addition, the absorption maxima listed for the IR spectra are those of interest, not all maxima observed.
In conjunction with the NMR spectra, the following abbreviations are used: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), multiplet (m), doublet of multiplets (dm), broad singlet (br.s), broad doublet (br.s), broad oriole: (br.t), and broad multiplet (br.m). J indicates the coupling constant in Hertz (Hz). Unless otherwise noted, NMR data refer to the free base of the subject compound.
The NMR spectra were obtained on a Bruker Corp. 270 MHz instrument or on a General Electric QE300 300 MHz instrument. The chemical shifts are expressed in delta values (ppm downfield from tetramethylsilane). MS(FD) spectra were taken on a Varian-MAT 731 Spectrometer using carbon dendrite emitters. EIMS spectra were obtained on a CEC 21-110 instrument from Consolidated Electrodynamics Corporation. MS(FAB) spectra were obtained on a VG ZAB-3 Spectrometer. IR spectra were obtained on a Perkin-Elmer 281 instrument. UV spectra were obtained on a Cary 118 instrument. TLC was carried out on E. Merck silica gel plates. Melting points are uncorrected.
Preparation 1
A. [3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2R*)]-2-[3xe2x80x2-N-(Benzyloxycarbonyl)amino-2xe2x80x2-hydroxy-4xe2x80x2-phenyl]butyl decahydroisoquinoline-3-N-t-butylcarboxamide
A solution of [1xe2x80x2S-(1xe2x80x2R*,1R*)]-1-[1xe2x80x2-N-(benzyloxycarbonyl)amino-2xe2x80x2-(phenyl)ethyl]oxirane and [3S-(3R*,4aR*,8aR*)]-decahydroisoquinoline-3-N-t-butylcarboxamide in absolute ethanol was heated at 80xc2x0 C. overnight. The reaction mixture was reduced to dryness under reduced pressure to provide a residue. This residue was purified using flash chromatography (gradient eluent of 10-50% ethyl acetate in methylene chloride) to provide 6.47 g of an off-white foam.
Yield: 75%.
1H NMR (CDCl3): xcex4 1.29 (s, 9H), 1.25-2.05 (m, 2H), 2.20-2.35 (m, 2H), 2.55-2.70 (m, 11H), 2.85-3.10 (m, 3H), 3.24 (br.s, 1H), 3.82 (br.s, 1H), 3.98 (br.s, 1H), 4.99 (br.s, 2H), 5.16-5.18 (m, 1H), 5.80 (br.s, 1H), 7.05-7.38 (m, 10H).
IR (CHCl3): 3600-3100 (br.), 3031, 2929, 1714, 1673, 1512, 1455, 1368, 1232, 1199, 1047 cmxe2x88x921.
MS(FD): m/e 536 (M+).
B. [3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2R*)]-2-[3xe2x80x2-Amino-2xe2x80x2-hydroxy-4xe2x80x2-phenyl]butyl decahydroisoquinoline-3-N-t-butylcarboxamide
A rapidly stirring suspension of 6.37 g (11.91 mmol) of the subtitled compound of Preparation 1A and 1.2 g of 10% palladium-on-carbon in 200 mL of absolute ethanol was placed under an atmosphere of hydrogen. After approximately 48 hours, the reaction mixture was filtered through celite and reduced to dryness under reduced pressure to provide 5.09 g of the desired subtitled compound. This compound was used without further purification.
1H NMR (CDCl3): xcex4 1.33 (5, 9H), 1.40-1.95 (m, 10H), 2.25-2.48 (m, 2H), 2.59-2.75 (m, 3H), 2.80-3.40 (m, 7H), 3.75-3.90 (m, 1H), 6.19 (br.s, 1H), 7.18-7.35 (m, 5H).
IR (CHCl3): 3600-3100 (br.), 2929, 2865, 1671, 1515, 1455, 1367, 1245, 1047 cmxe2x88x921.
MS(FD): m/e 402 (M+, 100).
Preparation 2
A. 2R-N(Benzyloxycarbonyl)amino-3-naphth-2-ylthio propanoic acid
To a solution of 1.28 g (8.00 mmol) of naphthalene-2-thiol in 30 mL of tetrahydrofuran, was slowly added 1.77 g (8.16 g) of 60% sodium hydride, under nitrogen. After stirring for approximately 15 minutes, a solution of N(benzyloxycarbonyl)serine-xcex2-lactone in 20 mL of tetrahydrofuran was slowly added. The reaction mixture was allowed to react at room temperature for approximately one hour, and then was concentrated under reduced pressure to provide a residue. This residue was dissolved in ethyl acetate and washed sequentially with 0.5N sodium bisulfate and a saturated brine solution. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a residue. This residue was purified using flash chromatography to provide 2.08 g of a pale yellow solid.
Yield: 68%.
1H NMR (CDCl3): xcex4 3.42-3.61 (br.m, 2H), 5.53-5.76 (br.s, 1H), 4.85-5.08 (br.m, 2H) , 5.54-5.76 (br.s, 1H), 7.06-7.97 (m, 12H).
[xcex1]D xe2x88x9255.72xc2x0 (c 1.0, MeOH).
IR (KBr): 3348, 3048, 1746, 1715, 1674, 1560, 1550, 1265, 1200, 1060 cmxe2x88x921.
MS(FD): m/e 381 (M+), 381 (100).
Analysis for C20H19NO4S: Calcd: C, 66.12; H, 5.02; N, 3.67; Found: C, 66.22; H, 5.04; N, 3.86.
B. 3R-1-Diazo-2-oxo-3-N-(benzyloxycarbonyl)amino-4xe2x80x2-(naphth-2-ylthio) butane
To a cold (xe2x88x9230xc2x0 C.) solution of 15.38 g (40.3 mmol) of the subtitled compound of Preparation 2A in 230 mL of ethyl acetate, was slowly added 5.62 mL (40.3 mmol) of triethylamine, under nitrogen via syringe. To the resulting solution was then added 7.84 mL (60.5 mmol) of isobutyl chloroformate, via syringe. In a separate flask, 10 g of N(methyl)-N(nitro)-N(nitroso)-guanidine was carefully added to a bilayer mixture of 170 mL of diethylether and 170 mL of a 5N sodium hydroxide solution, resulting in a large evolution of gas. When this reaction was substantially complete, the organic layer was decanted from the aqueous layer onto potassium hydroxide and dried. This diazomethane formation and addition was repeated using identical quantities of diethylether and sodium hydroxide and 30 g of N(methyl)-N(nitro)-N(nitroso)-guanidine. The resultant diazomethane reactant was then added to the mixed anhydride solution prepared above and the reaction mixture was allowed to react cold (xe2x88x9230xc2x0 C.) for approximately 20 minutes. When the reaction was substantially complete, as indicated by TLC, nitrogen was bubbled through the solution using a fire polished Pasteur pipet to remove any excess diazomethane and then the solution was concentrated under reduced pressure to provide a residue. This residue was purified using flash chromatography (eluent of 10% ethyl acetate in methylene chloride) to provide 13.62 g of a yellow oil.
Yield: 83%.
1H NMR (CDCl3) xcex4 3.32-3.46 (m, 2H), 4.40-4.67 (m, 1H), 5.00-5.09 (m, 2H), 5.44 (s, 1H), 5.76 (d, J=7.8 Hz, 1H), 7.25-7.86 (m, 12H).
C. 3R-1-Chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-(naphth-2-ylthio) butane
A short burst (about 2 seconds) of anhydrous hydrochloric acid (gas) was passed through a cold (xe2x88x9220xc2x0 C.) solution of 13.62 g (33.59 mmol) of the subtitled compound of Preparation 2B in 230 mL of diethylether, resulting in the evolution of a gas. This procedure was repeated taking care not to add excess hydrochloric acid. When the reaction was substantially complete, as indicated by TLC, the solution was concentrated under reduced pressure to provide a residue. This residue was purified using flash chromatography (eluent of 10% ethyl acetate in methylene chloride) to provide 12.05 g of a pale tan solid.
Yield: 87%.
1NMR (CDCl3): xcex4 3.41 (dd, J=12,6 Hz, 1H), 3.53 (dd, J=12,6 Hz, 1H), 4.18 (AB q, J=41.9 Hz, J=15.9 Hz, 2H), 4.77 (dd, J=9, 3 Hz, 1H), 5.04 (AB q, J=12 Hz, J=10.4 Hz, 2H), 5.59 (d, J=7 Hz, 1H), 7.24-7.85 (m, 12H).
[xcex1]D xe2x88x9280.00xc2x0 (c 1.0, MeOH).
IR (CHCl3): 3426, 3031, 3012, 1717, 1502, 1340, 1230, 1228, 1045 cmxe2x88x921.
MS(FD): m/e 413 (M+), 413 (100).
Analysis for C22H20NO3SCl: Calcd: C, 63.84; H, 4.87; N, 3.38; Found: C, 64.12; H, 4.95; N, 3.54.
D. [3R-fixed(3R*,4S*)]-1-Chloro-2-hydroxy-3-N-(benzyloxycarbonyl)amino-4-(naphth-2-ylthio) butane
To a cold (0xc2x0 C.) solution of 530 mg (1.28 mmol) of the subtitled compound of Preparation 2C, in 10 mL of tetrahydrofuran and 1 mL of water, was added 73 mg (1.92 mmol) of sodium borohydride. When the reaction was substantially complete as indicated by TLC, the solution was adjusted to pH 3 using 10 mL of an aqueous saturated ammonium chloride solution and 500 xcexcL of a 5N hydrochloric acid solution. The resultant solution was extracted twice with methylene chloride and the combined organic layers were washed with water, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (eluent of methylene chloride) to provide 212 mg of a tan solid.
Yield: 40%.
1H NMR (CDCl3): xcex4 3.40 (s, 2H), 3.61-3.71 (m, 2H), 3.97-3.99 (m, 2H), 4.99 (s, 2.H), 5.16 (br.s, 1H), 7.21-7.83 (complex, 12H).
MS(FD): m/e 415 (M+), 415 (100). [xcex1]D xe2x88x9247.67xc2x0 (c 0.86, MeOH).
IR (CHCl3): 3630, 3412, 3011, 1720, 1502, 1236, 1044 cmxe2x88x921.
Analysis for C22H22 NO3ClS: Calcd: C, 63.53; H, 5.33; N, 3.37; Found: C, 63.72; H, 5.60; N, 3.64.
E. [1xe2x80x2R-(1xe2x80x2R*,1S*)]-1-[(1xe2x80x2-N-(Benzyloxycarbonyl)amino-2xe2x80x2-(naphth-2-ylthio)ethyl] oxirane
A solution of 31 mg (0.55 mmol) of potassium hydroxide in 1 mL of ethanol was added to a solution of 190 mg (0.46 mmol) of the subtitled compound of Preparation 2D, in 6 mL of a 1:2 ethanol/ethyl acetate solution. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was poured into a water/methylene chloride mixture. The resulting layers were separated, and the organic layer was washed with water, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (eluent of 10% ethyl acetate in methylene chloride) to provide 172 mg of a light tan solid.
Yield: 99%.
1H NMR (CDCl3): xcex4 2.76 (br.s, 2H) 3.01 (br.s, 1H), 3.31 (d, J=5 Hz, 2H), 3.77 (br.s, 1H), 5.05 (s, 2H), 5.22 (d, J=6 Hz, 1H), 7.25-7.85 (complex, 12H).
[xcex1]D xe2x88x92125.42xc2x0 (c 0.59, MeOH).
MS(FD): m/e 379 (M+), 379 (100).
IR (CHCl3): 3640, 3022, 2976, 1720, 1502, 1235, 1045 cmxe2x88x921.
Analysis for C22H21NO3S: Calcd: C, 69.63; H, 5.58; N, 3.69; Found: C, 69.41; H, 5.53; N, 3.64.
F. [2S-(2R*,2xe2x80x2R*,3xe2x80x2S*)]-1-[2xe2x80x2-Hydroxy-3xe2x80x2-(N-benzyloxycarbonyl)amino-4xe2x80x2-(naphth-2-ylthio)butyl] piperidine-2-N-(t-butyl)carboxamide
A solution of 0.51 g (1.34 mmol) of the subtitled compound of Preparation 2E and 0.26 g (1.41 mmol) of the subtitled compound of Preparation 4C in 25 mL of isopropanol was heated to 55xc2x0 C. for approximately forty eight hours. The resultant reaction mixture was cooled and then concentrated under reduced pressure to provide a crude material. This material was purified using radial chromatography (4 mm plate; eluent of 10% acetone in methylene chloride) to provide 104 mg of a white foam.
Yield: 14%.
1H NMR (CDCl3): xcex4 1.29 (s, 9H), 1.44-1.82 (m, 6H), 2.19 (m, 1H), 2.40 (m, 1H), 2.68 (m, 2H), 3.09 (m, 1H), 3.46 (m, 2H), 4.00 (m, 2H), 5.01 (s, 2H), 5.73 (d, 1H), 6.01 (br.s, 1H), 7.23-7.34 (m, 5H), 7.45 (m, 3H), 7.72-7.83 (m, 4H).
MS(FD): m/e 563 (M+, 100).
G. [2S-(2R*,2xe2x80x2S*,3xe2x80x2S*)]-1-(2xe2x80x2-Hydroxy-3xe2x80x2-amino-4xe2x80x2-(naphth-2-ylthio)butyl] piperidine-2-N-(t-butyl)carboxamide
A solution containing 1.05 g (0.18 mmol) of the subtitled compound of Preparation 2F in 10 mL of 30% hydrobromic acid in acetic acid was reacted for approximately one hour. The resultant reaction mixture was concentrated, azeotroped three times with toluene, redissolved in methanol containing 4.5 mL each of diethylamine and ammonium hydroxide and then concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (1 mm plate; eluent of 3% methanol in methylene chloride containing 1% acetic acid) to provide 64 mg of a white foam.
Yield: 80%.
1H NMR (CDCl3) xcex4 1.29 (s, 9H), 1.52-1.73 (m, 6H), 1.84 (m, 1H), 2.31-2.43 (m, 2H), 2.75-3.04 (m, 5H), 3.17 (m, 1H), 3.41 (m, 1H), 3.71 (m, 1H), 6.22 (br.s, 1H), 7.47 (m, 3H), 7.73-7.82 (m, 4H).
MS(FD): m/e 430 (M+, 100).
Preparation 3
A. 2S-N-(Benzyloxycarbonyl)-2-pyrrolidinecarboxylate pentafluorophenyl ester
To a cold (0xc2x0 C.) solution of 30 g (0.12 mol) of 2S-N(benzyloxycarbonyl)-2-pyrrolidinecarboxylic acid and 25.8 g (0.14 mol) of pentafluorophenol in 450 mL of tetrahydrofuran, was added 27.7 g (0.14 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) in one portion, followed by 150 mL of methylene chloride. The resultant reaction mixture was warmed to room temperature and reacted for approximately four hours. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated under reduced pressure to provide a residue. This residue was dissolved in 500 mL of ethyl acetate and washed sequentially with water, potassium carbonate, 1N hydrochloric acid and brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide a solid. This solid was redissolved in hexane and washed with potassium carbonate, dried over sodium sulfate, filtered and reduced to dryness under reduced pressure to provide 45:95 g of the desired subtitled compound.
Yield: 92%.
1H NMR (CDCl3): xcex4 1.95-2.15 (m, 2H), 2.20-2.35 (m, 1H), 2.35-2.50 (m, 1H), 3.50-3.75 (m, 2H), 4.65-4.75 (m, 1H), 5.02-5.30 (m, 2H), 7.20-7.45 (m, 5H).
B. 2S-N-(Benzyloxycarbonyl)pyrrolidine-2-N(t-butyl)carboxamide
To a cold (0xc2x0 C.) solution of 45.90 g (0.111 mmol) of the subtitled compound of Preparation 3A in 100 mL of anhydrous methylene chloride, was slowly added 100 mL (0.952 mmol) of t-butylamine. The reaction mixture was warmed to room temperature and reacted for approximately one hour and then diluted with 1000 mL of methylene chloride and then washed sequentially with 1N potassium carbonate, 1N hydrochloric acid, 1N potassium carbonate, and brine, dried, over sodium sulfate, and then plug filtered using 50% ethyl acetate in hexane to provide 37.74 g of the desired compound which was used without further purification.
1H NMR (CDCl3): . xcex4 0.95-1.50 (m, 9H), 1.70-2.40 (m, 4H), 3.30-3.60 (m, 2H), 4.10-4.30 (m, 1H), 4.95-5.35 (m, 2H), 5.65 (br.s, 0.5H), 6.55 (br.s, 1H), 7.20-7.50 (m, 5.5H).
C. 2S-Pyrrolidine-2-N-(t-Butyl)carboxamide
The subtitled compound of Preparation 3B (2.71 g, 8.9 mmol) was deprotected substantially as detailed in Preparation 1B, using 500 mg of 10% palladium-on-carbon and hydrogen gas (1 atmosphere) in 200 mL of ethanol.
Yield: 1.53 g (100%).
1H NMR (CDCl3): xcex4 1.35 (s, 9H), 1.60-1.75 (m, 2H), 1.76-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.58 (br.s, 1H), 2.80-3.05 (m, 2H), 3.55-3.65 (m, 1H), 7.45 (br.s, 1H).
D. [2S-(2R*, 2xe2x80x2S*,3xe2x80x2R*)]-1-[3xe2x80x2-N(Benzyloxycarbonyl)-amino-2xe2x80x2-hydroxy-4xe2x80x2-phenylbutyl] pyrrolidine-2-N-(t-butyl)carboxamide
A solution containing 122 mg (0.72 mmol) of the subtitled compound of Preparation 3C and 200 mg (0.68 mmol) of [1S-(1R*,1R*)]-1-[(1xe2x80x2-N-(benzyloxycarbonyl)amino-2xe2x80x2-phenyl)ethyl]oxirane in 10 mL of methanol was stirred overnight. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated under reduced pressure. The desired compound was purified using column chromatography (gradient eluent of 2-4% methanol in methylene chloride) to provide 232.2 mg of a clear amorphous solid.
Yield: 55%.
[xcex1]D xe2x88x9256.97xc2x0 (c=0.27, MeOH).
1H NMR (CDCl3): xcex4 1.33 (s, 9H) 1.55-1.95 (m, 4H), 2.05-2.25 (m, 1H), 2.40-2.55 (m, 1H), 2.65-2.75 (m, 2H), 2.80-3.00 (m, 3H), 3.15-3.30 (m, 1H), 3.65-3.75 (m, 1H), 3.85-3.95 (m, 1H), 4.86 (br.d, J=1.1 Hz, 1H), 5.03 (s, 2H), 6.95 (m, 1H), 7.15-7.40 (m, 10H).
IR (CHCl3): 3700-3100 (br.), 3434, 3031, 2976, 1720, 1664, 1604, 1512, 1455, 1394, 1367, 1343, 1233, 1156, 1107, 1063, 1028, 911 cmxe2x88x921.
MS(FD): m/e 468 (M+, 100)
E. [2S-(2R*,2xe2x80x2S*,3xe2x80x2R*)]-1-[3xe2x80x2-Amino-2xe2x80x2-hydroxy-4xe2x80x2-phenylbutyl] pyrrolidine-2-N-t-butylcarboxamide
The subtitled compound of Preparation 3D (222 mg, 0.47 mmol) was deprotected substantially as detailed in Preparation 1B, using 67 mg of 10% palladium-on-carbon and hydrogen gas (1 atmosphere) in 15 mL of ethanol. The desired compound was purified using column chromatography (eluent of 10% isopropanol in methylene chloride containing 0.75% ammonium hydroxide) to provide 80 mg of an off-white solid.
Yield: 51%.
[xcex1]D xe2x88x9255.26xc2x0 (c=0.23, MeOH).
1H NMR (CDCl3): xcex4 0.80-3.70 (m, 25H), 6.90-7.40 (m, 6H).
IR (CHCl3): 3692, 3600-3200 (br.), 2975, 1657, 1603, 1522, 1497, 1479, 1455, 1393, 1366, 1232, 1198, 1137, 1049, 882 cmxe2x88x921.
MS(FD): m/e 334 (M+, 100).
Preparation 4
A. 2S-N-(t-Butoxycarbonyl) piperidine-2-carboxylic acid
A solution of 1.64 g of sodium carbonate in 15 ml of water was added to a cold (0xc2x0 C.) solution of 2.0 g (15.5 mol) of 2S-piperidinecarboxylic acid in 50 mL of dioxane. After approximately ten minutes, 3.7 g (17.0 mol) of di-t-butyl dicarbonate was added to the mixture. The resultant reaction mixture was reacted for approximately six hours, concentrated to one fourth of the original volume and then acidified to pH 2 using 1M sodium hydrogen sulfate and ethyl acetate. The resulting layers were separated, and the organic layers were washed with a saturated brine solution, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 2.67 g of a white crystalline solid.
Yield: 75%.
[xcex1]D xe2x88x9255.26xc2x0 (c=0.23, MeOH).
1H NMR (CDCl3): xcex4 1.20-1.80 (m, 15H), 2.15-2.30 (m, 1H), 2.85-3.10 (m, 1H), 3.90-4.10 (m, 2H), 4.70-5.00 (m, 1H).
IR (CHCl3): 3700-1800 (br.), 3025, 3018, 3011, 2980, 2947, 2865, 1716, 1685, 1449, 1394, 1368, 1280, 1252, 1162, 1147, 1129 cmxe2x88x921.
MS(FD): m/e 229 (M+, 100).
Analysis for C27H37N3O4: Calcd: C, 57.63; H, 8.35; N, 6.11; Found: C, 57.90; H, 8.35; N, 6.19.
B. 2S-N-(t-Butoxycarbonyl) piperidine-2-carboxylate, pentafluorophenylester
To a cold (0xc2x0 C.) solution of 2.53 g (11.03 mol) of the subtitled compound of Preparation 4A and 2.34 g (12.7 mol) of pentafluorobenzoic acid in 50 mL of tetrahydrofuran, was added 2.42 g (12.7 mol) of EDC. The resultant reaction mixture was warmed to room temperature and reacted for approximately two hours. The mixture was then concentrated under reduced pressure to provide a solid. This solid was redissolved in methylene chloride and washed sequentially with potassium carbonate and brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 3.85 g of a clear oil which solidified on standing.
Yield: 88%.
1H NMR (CDCl3): xcex4 1.20-1.90 (m, 15H), 2.30-2.40 (m, 1H), 2.90-3.15 (m, 1H), 3.90-4.15 (m, 1H), 5.05-5.35 (m, 1H).
C. 2S-N-(t-Butoxycarbonyl) piperidine-2-N-t-butylcarboxamide
To a cold (0xc2x0 C.) solution of 3.8 g (9.6 mmol) of the subtitled compound of Preparation 4B in 200 mL of methylene chloride, was slowly added 2.53 mL (24.0 mmol) of t-butylamine. The reaction mixture was reacted for approximately four hours and then concentrated under reduced pressure to provide a residue. This residue was redissolved in methylene chloride and then washed sequentially with 1M potassium carbonate and brine, dried over sodium sulfate, filtered and then purified Using column chromatography (gradient eluent of 10-20% ethyl acetate in hexane) to provide 2.52 g of a white solid.
Yield: 92%.
[xcex1]D xe2x88x9241.47xc2x0 (c=0.506, MeOH).
1H NMR (CDCl3): xcex4 1.10-1.70 (m, 15H), 2.20-2.35 (m, 1H), 2.65-2.82 (m, 1H), 3.90-4.10 (m, 1H), 4.62 (br.s, 1H).
IR (CHCl3): 3600-3300 (br.), 2978, 2945, 2869, 1677, 1512, 1455, 1413, 1394, 1367, 1317, 1280, 1255, 1162, 1144, 1127, 1078, 1042, 868 cmxe2x88x921.
MS(FD): m/e 284 (M+, 100).
Analysis for C15H28N2O3: Calcd: C, 63.35; H, 9.92; N, 9.85; Found: C, 63.10; H, 9.66; N, 9.92.
D. 2S-Piperidine-2-N-t-butylcarboxamide
A solution containing 1.0 g (3.5 mol) of the subtitled compound of Preparation 4C and 3.5 mL of trifluoroacetic acid in 25 mL of methylene chloride was stirred at room temperature for approximately two hours. The reaction mixture was concentrated and azeotroped once with toluene. The resultant reaction mixture was then partitioned between methylene chloride and sodium bicarbonate. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and reduced to dryness under reduced pressure to provide 641 mg of the subtitled compound.
Yield: 99%.
[xcex1]D xe2x88x9222.45xc2x0 (c=0.95, MeOH).
1H NMR (CDCl3): xcex4 1.20-1.50 (m, 12H), 1.51-1.62 (m, 1H), 1.64 (s, 1H), 1.75-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.72 (m, 1H), 2.98-3.10 (m, 2H), 6.63 (br.s, 1H).
IR (CHCl3): 3363, 3002, 2969, 2940, 2860, 1738, 1660, 1522, 1480, 1455, 1398, 1367, 1324, 1295, 1230, 1129, 1110, 852 cmxe2x88x921.
MS(FD): m/e 184 (M+, 100).
E. [2S-(2R*,2xe2x80x2S*,3xe2x80x2R*)]-N-[3xe2x80x2-(N-Benzyloxycarbonyl)amino-2xe2x80x2-hydroxy-4xe2x80x2-phenyl]butyl piperidine-2-N-t-butylcarboxamide
A solution containing 195 mg (1.06 mmol) of the subtitled compound of Preparation 4D and 300 mg (1.01 mmol) of [1S-(1R*,1xe2x80x2R*)]-1-[(1xe2x80x2-N(benzyloxycarbonyl)amino-2xe2x80x2-phenyl)ethyl]oxirane in 10 mL of isopropanol was stirred at 55xc2x0 C. for approximately forty eight hours. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated under reduced pressure. The desired compound was purified using column chromatography (gradient eluent of 1-5% isopropanol in methylene chloride).
Yield: 395 mg (81%).
[xcex1]D xe2x88x9255.64xc2x0 (c=0.22, MeOH).
1H NMR (CDCl3): xcex4 1.32 (s, 9H), 1.45-1.90 (m, 6H), 2.25-2.50 (m, 2H), 2.70-3.20 (m, 5H), 3.30-3.40 (m, 1H), 3.75-4.05 (m, 2H), 4.95-5.10 (m, 3H), 6.15 (br.s, 1H), 7.18-7.40 (m, 10H).
IR (CHCl3): 3700-3100 (br.), 3623, 3021, 2976, 1668, 1603, 1511, 1456, 1313, 1047, 878 cmxe2x88x921.
MS(FD): m/e 482 (M+, 100).
F. [2S-(2R*,2xe2x80x2S*,3xe2x80x2R*)]-N-[3xe2x80x2-Amino-2xe2x80x2-hydroxy-4xe2x80x2-phenyl]butyl piperidine-2-N-t-butylcarboxamide
The subtitled compound of Preparation 4E (371 mg, 0.77 mmol was deprotected substantially as detailed in Preparation 1B, using 110 mg of 10% palladium-on-carbon and hydrogen gas in 20 mL of ethanol to provide 260 mg of a white foam.
Yield: 97%.
[xcex1]D xe2x88x9264.92xc2x0 (c=0.39, MeOH).
1H NMR (CDCl3) xcex4 1.35 (s, 9H), 1.45-1.90 (m, 6H), 2.25-2.35 (m, 1H), 2.50-2.90 (m, 5H), 3.00-3.40 (m, 3H), 3.85-3.98 (m, 1H), 6.29 (s, 1H), 7.15-7.38 (m, 5H).
IR (CHCl3): 3693, 3650-3100 (br.), 2943, 2862, 1671, 1603, 1517, 1497, 1455, 1394, 1367, 1233, 1185, 1049, 887 cmxe2x88x921.
MS(FD): m/e 348 (M+, 100).
Preparation 5
A. Pyrazine-2-N-(t-butyl)carboxamide
To a slurry of 50 g (0.403 mol) pyrazine-2-carboxylic acid in 600 mL of tetrahydrofuran and 100 mL of dimethylformamide, was added 65.9 g (0.407 mol) of carbonyldiimidazole. The resultant reaction mixture was reacted at 50xc2x0 C. until gas evolution ceased. After the reaction mixture cooled, 73.5 g (1.00 mol) of t-butylamine was slowly added. The reaction mixture was reacted for approximately thirty minutes, concentrated under reduced pressure, redissolved in 500 mL of methylene chloride and then washed sequentially with water, hydrochloric acid (pH 2), saturated sodium bicarbonate, water, 1M potassium hydroxide, and brine, dried over sodium sulfate, and concentrated to provide 68.5 g of a white solid.
Yield: 95%.
1H NMR (CDCl3): xcex4 1.51 (s, 9H), 7.73 (br.s, 1H), 8.49 (m, 1H), 8.72 (m, 1H), 9.38 (s, 1H).
B. (+/xe2x88x92)-Piperazine-2-N-(t-butyl)carboxamide
A mixture of 68.5 g (0.382 mol) of the subtitled compound of Preparation 5A, 70 g (0.308 mol) of platinum oxide in 186 mL of ethanol was heated overnight at 40xc2x0 C. under a hydrogen atmosphere (60 psi). The resultant crude material was filtered and the filtrate was concentrated to provide 65 g of white solid.
Yield: 95%.
MS(FD): m/e 185 (M+, 100).
C. (+/xe2x88x92)-4-(Pyrid-3xe2x80x2-ylmethyl)piperazine-2-N-(t-butyl)carboxamide
To a solution of 5.0 g (0.027 mol) of the subtitled compound of Preparation 5B in 160 mL of a 1:1 mixture of water and acetonitrile, was added 18.65 g (0.135 mol) of potassium carbonate. The resultant mixture was vigorously stirred during the addition of 4.43 g (0.027 mol) of 3-chloromethylpyridine hydrochloride and then allowed to react overnight. The resultant reaction mixture was concentrated under reduced pressure, slurried in a solution of 20% isopropanol in chloroform and washed sequentially with water and brine, dried over sodium sulfate, filtered and then concentrated to provide a residue. This residue was purified using flash chromatography (eluent of 5% methanol in methylene chloride containing 1% ammonium hydroxide) to provide 1.34 g of a clear yellow oil.
Yield: 18%.
1H NMR (CDCl3): xcex4 1.10 (s, 9H), 1.89-2.01 (m, 2H), 2.35 (m, 1H), 2.57-2.74 (m, 4H), 3.09 (m, 1H), 3.27 (s, 2H), 6.71 (br.s, 1H), 7.03 (m, 1H), 7.44 (m, 1H) 8.26 (m, 2H).
IR (KBr): 3691, 3611, 3366, 2974, 1666, 1602, 1521, 1479, 1456, 1427, 1393, 1366, 1324, 1139, 1047, 839 cmxe2x88x921.
MS(FD): m/e 276 (M+, 100).
D. [2S-(2R*,2xe2x80x2S*,3xe2x80x2R*)]-1-[2xe2x80x2-Hydroxy-3xe2x80x2-(N-benzyloxycarbonyl)amino-4xe2x80x2-phenylbutyl]-4-(pyrid-3xe2x80x3-ylmethyl) piperazine-2-N-(t-butyl)carboxamide
A solution containing 0.377 g (1.27 mmol) of [1S-(1R*,1xe2x80x2R*)]-1-[(1xe2x80x2-N-Benzyloxycarbonyl)amino-2xe2x80x2-phenyl)ethyl]oxirane and 0.350 g (1.27 mmol) of the subtitled compound of Preparation 5C in 12 mL of isopropanol was reacted at 45xc2x0 C. for approximately forty eight hours. The reaction mixture was cooled and then concentrated under reduced pressure to provide a crude material. This material was purified using radial chromatography (6 mm plate; gradient eluent of 5-10% isopropanol in methylene chloride) to provide 120 mg of isomer A and 68 mg of isomer B.
Yield: 26% overall.
Isomer A:
1H NMR (CDCl3): xcex4 1.33 (s, 9H), 2.26-2.89 (m, 13H), 3.29 (m, 1H), 3.45 (s, 2H), 3.79-3.95 (m, 3H), 4.73 (br.s, 1H), 4.97 (br.s, 2H), 5.20 (m, 1H), 7.14-7.29 (m, 6H) 7.57 (m, 1H), 7.82 (br.s, 1H), 8.53 (m, 2H).
IR (KBr): 3692, 3434, 2970, 2829, 1714, 1661, 1604, 1579, 1512, 1455, 1427, 1393, 1365, 1231, 1149, 1029, 909 cmxe2x88x921.
MS(FD): m/e 573 (M+, 100).
E. [2S-(2R*,2xe2x80x2S*,3xe2x80x2R*)]-1-[2xe2x80x2-Hydroxy-3xe2x80x2-amino-4xe2x80x2-phenyl]butyl-4-(pyrid-3xe2x80x3-ylmethyl) piperazine-2-N-(t-butyl)carboxamide
A solution containing 0.062 g (0.11 mmol) of the subtitled compound of Preparation 5D (isomer A) was stirred for approximately ninety minutes in 1.5 mL of a solution of 30% hydrobromic acid in acetic acid. The resultant mixture was concentrated, azeotroped three times with toluene, redissolved in methanol containing 1 mL each of diethylamine and ammonium hydroxide and then concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (2 mm plate; gradient eluent of 15-25% methanol in methylene chloride containing 1% ammonium hydroxide) to provide 13 mg of a white solid.
Yield: 28%.
1H NMR (CDCl3): xcex4 1.33 (s, 9H), 2.36-3.21 (m, 15H), 3.47 (d, 2H), 3.75 (m, 1H), 7.19-7.30 (m, 6H) 7.57 (m, 2H), 8.52 (m, 2H).
MS(FD): m/e 440 (M+, 100).
Preparation 6
A. [2S-(2R*,2xe2x80x2S*,3xe2x80x2S*)]-1-[3xe2x80x2-N-(Benzyloxycarbonyl)amino-2xe2x80x2-hydroxy-4xe2x80x2-phenylthiobutyl]-4-[pyrid-3xe2x80x3-ylmethyl] piperazine-2-N-t-butylcarboxamide [isomer B]
A solution of 596 mg (1.81 mmol) of [1S-(1R*,1xe2x80x2S*)]-1-[1xe2x80x2-N-(benzyloxycarbonyl)amino-2xe2x80x2-(phenylthio)ethyl]oxirane and 500 mg (1.81 mmol) of the subtitled compound of Preparation 5C in 15 mL of isopropanol were heated at 43xc2x0 C. for approximately forty-eight hours. The reaction was monitored using TLC (10% isopropanol in methylene chloride containing 1% ammonium hydroxide; Isomer A Rf=0.7; Isomer B Rf=0.6). When the reaction was substantially complete, the reaction mixture was concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (6 mm plate; gradient eluent of 5-15% isopropanol in methylene chloride containing 1% ammonium hydroxide) to provide 200 mg of isomer A as a light tan foam and 119 mg of an off-white foam (isomer B).
Isomer A:
Yield: 18%.
1NMR (CDCl3): xcex4 1.31 (s, 9H), 2.25-2.62 (m, 7H), 2.78-2.95 (m, 2H), 2.98-3.08 (m, 1H), 3.10-3.25 (m, 2H), 3.40-3.55 (m, 2H), 3.72-3.85 (m, 1H), 3.90-4.00 (m, 1H), 5.05 (s, 2H), 7.01 (br.s, 1H), 7.10-7.40 (m, 11H), 7.62 (d, J=7.8 Hz, 1H), 8.49 (s, 2H).
MS(FD): m/e 606 (M+, 100).
Analysis for C33H43N5O4S: Calcd: C, 65.42; H, 7.15; N, 11.56; Found: C, 65.38; H, 7.27; N, 11.36.
Isomer B:
Yield: 11%.
1H NMR (CDCl3): xcex4 1.33 (s, 9H), 2.25-2.85 (m, 8H), 3.20-3.32 (m, 3H), 3.47 (s, 2H), 3.78-3.95 (m, 2H), 5.06 (s, 2H), 5.30-5.38 (m, 1H), 7.10-7.42 (m, 12H), 7.55-7.85 (m, 2H), 8.50-8.60 (m, 2H).
MS(FD): m/e 606 (M), 497 (100).
HR MS(FAB) for C33H44N5O4S: Calcd: 606.3114; Found: 606.3141.
B. [2S-(2R*,2xe2x80x2S*,3xe2x80x2S*)]-1-[2xe2x80x2-Hydroxy-3xe2x80x2-amino-4xe2x80x2-phenylthiobutyl]-4-[pyrid-3xe2x80x3-ylmethyl] piperazine-2-N-t-butylcarboxamide
A solution of 110 mg (0.18 mmol) of isomer B from Preparation 6A in 5 mL of 30% hydrobromic acid in acetic acid was stirred at room temperature for approximately 1 hour. The reaction mixture was concentrated under reduced pressure to provide a residue. This residue was redissolved in 4 mL of ammonium hydroxide. The resultant solution was extracted four times with 10 mL portions of a 10% solution of isopropanol in chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrate under reduced pressure to provide a residue. This residue was purified using radial chromatography (2 mm plate; gradient eluent of 10-30% methanol in methylene chloride containing 1% ammonium hydroxide) to provide 65 mg of a light yellow foam.
Yield: 72%.
1H NMR (CDCl3): xcex4 1.25 (s, 9H), 2.25-2.78 (m, 7H), 3.00-3.32 (m, 4H), 3.47 (s, 2H), 3.60-3.75 (m, 1H), 4.18-4.35 (m, 1H), 6.90-7.65 (m, 9H), 8.40-8.60 (m, 2H).
MS(FD): m/e 473 (M+, 100).
Preparation 7
A. [3S-(3R*, 4aR*,8aR* ,2xe2x80x2S*,3xe2x80x2S*)]-2-[3-N-(Benzyloxycarbonyl)amino-2xe2x80x2-hydroxy-4xe2x80x2-(naphth-2-ylthio)]butyl decahydroisoquinoline-3-N-(t-butyl)carboxamide
A solution was prepared containing 165 mg (0.40 mmol) of the subtitled intermediate of Preparation 2E and 94 mg (0.43 mmol) of 3-(1-N(t-butyl)amino-1-oxomethyl) octahydro-(2H)-isoquinoline in 5 mL of ethanol. The resulting reaction mixture was allowed to react at 80xc2x0 C. for approximately 19 hours. The solution was then cooled to room temperature and concentrated under reduced pressure to provide a residue. This residue was purified using radial chromatography (eluent of 10% ethyl acetate in methylene chloride) to provide 103 mg of an off-white foam.
Yield: 42%.
1H NMR (CDCl3): xcex4 1.10-1.73 (m, 20H), 2.13-2.31 (m, 2H), 2.44-2.53 (m, 1H), 2.56-2.68 (m, 1H), 2.86-2.97 (m, 1H), 3.52 (br.s, 2H), 4.02 (br.s, 2H), 4.98 (s, 2H), 5.65 (s, 1H), 5.94 (s, 1H), 7.25-7.83 (complex, 13H).
MS(FD): m/e 629 (M+), 138 (100). [xcex1]D xe2x88x9292.45xc2x0 (c 1.06, MeOH).
IR CHCl3): 3429, 3010, 2929, 1713, 1670, 1514, 1455, 1047 cmxe2x88x921.
Analysis for C35H47N3O4S: Calcd: C, 69.98; H, 7.67; N, 6.80; Found: C, 69.86; H, 7.78; N, 6.58.
B. [3S -(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[3xe2x80x2-amino-2xe2x80x2-hydroxy-4xe2x80x2-(naphth-2-ylthio)]butyl decahydroisoquinoline-3-N-(t-butyl)carboxamide
A solution was prepared containing 50 mg (0.081 mmol) of the subtitled intermediate of Preparation 7A and 1 mL of a 38% aqueous hydrobromic acid solution in acetic acid. The resultant reaction mixture was allowed to react at room temperature for approximately 1 hour and then was concentrated under reduced pressure to provide a residue. This residue was slurried with toluene and then concentrated under reduced pressure to provide 61 mg of the desired subtitled intermediate. This compound was used crude without purification in Example 9.
1H NMR (CDCl3): xcex4 1.14 (s, 1H), 1.17-2.07 (complex, 15H), 2.66-2.87 (m, 2H), 3.21-3.25 (m, 2H), 3.75 (d, J=12 Hz, 1H), 3.85 (d, J=6 Hz, 1H), 4.36-4.47 (m, 1H), 6.73 (s, 1H), 7.39-7.90 (complex, 7H).
MS(FD): 483 (M+), 483 (100).
Preparation 8
A. 2R-2-N(Benzyloxycarbonyl)amino-3-phenylthio propanoic acid
To desired subtitled intermediate was prepared substantially in accordance with the procedure detailed in Procedure 2A, using 13.1 mL (127 mmol) of thiophenol, 4.6 g (117 mmol) of a 60% sodium hydride solution and 25.6 g (116 mmol) of L-N(benzyloxycarbonyl)-serine xcex2-lactone in 450 mL of tetrahydrofuran to provide a residue. This residue was purified using flash chromatography (gradient eluent of 0-2% acetic acid in a 4:1 methylene chloride/ethyl acetate mixture) to provide 27.9 g of a white solid.
Yield: 72%.
1H NMR (CDCl3): xcex4 7.55-7.18 (m, 10H), 5.55 (d, J=7 Hz, 1H), 5.08 (s, 2H), 4.73-4.60 (m, 1H), 3.55-3.30 (m, 2H).
IR (KBr): 3304, 3035, 1687, 1532, 736 cmxe2x88x921.
MS(FD): m/e 332, 288, 271, 181.
Analysis for C17H17NO4S: Calcd: C, 61.61; H, 5.17; N, 4.23; Found: C, 61.69; H, 5.22; N, 4.47.
B. 3S-1-Diazo-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthio butane
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2B, using 12.1 g (37 mmol) of the subtitled compound of Preparation 8A, 5.09 mL (37 mmol) of triethylamine, 7.13 mL (55 mmol) isobutyl chloroformate, 146 mmol of a diazomethane solution to provide a residue. The diazomethane solution was prepared using 100 mL of diethylether, 150 mL of a 5N sodium hydroxide solution and 21 g (146 mmol) of N(methyl)-N(nitro)-N(nitroso)-guanidine as described in Preparation 2B. This residue was purified using flash chromatography (gradient eluent of 0-5% ethyl acetate in methylene chloride) to provide a yellow oil.
Yield: 73%.
1NMR (CDCl3): xcex4 7.50-7.19 (m, 10H), 5.62 (d, J=7 Hz, 1H), 5.47 (br.s, 1H), 5.11 (s, 2H), 4.50-4.32 (m, 1H), 3.33 (d, J=6 Hz, 1H).
IR (KBr): 3012, 2115, 1720, 1501, 1367, 1228 cmxe2x88x921.
MS(FD): m/e 356, 328, 242.
C. 3R-1-Chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthio butane
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2C, using 22.3 g (63 mmol) of the subtitled compound of Preparation 8B and small quantities of hydrochloric acid (gas) in 400 mL of diethylether to provide 21 g of a white solid. This solid was used without further purification.
1H NMR (CDCl3): xcex4 7.50-7.15 (m, 10H) 5.56 (dd, J=2, 6.7 Hz, 1H), 5.11 (s, 2H), 4.78-4.67 (m, 1H), 4.20 (d, J=15.9 Hz, 1H), 4.12 (d, J=15.9 Hz, 1H), 3.48-3.23 (m, 2H).
IR (KBr): 3349, 1732, 1684, 1515, 1266 cmxe2x88x921.
MS(FD): m/e 363 (M+).
Analysis for C18H18NO3SCl: Calcd: C, 59.42; H, 4.99; N, 3.85; Found: C, 59.57; H, 5.09; N, 4.13.
D. [2S-(2R*,3S*)]-1-Chloro-2-hydroxy-3-N-(benzyoxycarbonyl)amino-4-phenylthio butane
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2D, using 21 g (58 mmol) of the subtitled compound of Preparation 8C, and 2.4 g (63 mmol) of sodium borohydride in 300 mL of tetrahydrofuran to provide a residue. This residue was purified using flash chromatography (gradient eluent of 0-2% methanol in methylene chloride) followed by flash chromatography (gradient eluent of 0-2% ethyl acetate in chloroform) and then recrystallized from methylene chloride at xe2x88x9278xc2x0 C. to provide 8.3 g of the subtitled compound.
Yield: 39%.
1H NMR (CDCl3): d 7.47-7.19 (m, 10H), 5.22-5.03 (m, 1H), 5.09 (s, 2H), 4.01-3.89 (m, 2H), 3.75-3.58 (m, 2H), 3.32 (d, J=4 Hz, 2H).
IR (KBr): 3321, 2951, 1688, 1542, 1246, 738 cmxe2x88x921.
MS(FD): m/e 366 (M+), 119.
Analysis for C18H20NO3SCl: Calcd: C, 59.09; H, 5.51; N, 3.83; Found: C, 59.03; H, 5.50; N, 3.96.
E. [1xe2x80x2R-(1xe2x80x2R*,1S*)]-1-[(1xe2x80x2-N-(benzyoxycarbonyl)amino-2xe2x80x2-phenylthio)ethyl oxirane
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2E, using 8.3 g (23 mmol) of the subtitled compound of Preparation 8D, 1.4 g (25 mmol) of potassium hydroxide in 400 mL of ethanol to provide a residue. This residue was purified using flash chromatography (gradient eluent of 0-2% ethyl acetate in methylene chloride) to provide 6.4 g of a white solid.
Yield: 85%.
1H NMR (CDCl3): xcex4 7.45-7.15 (m, 10H), 5.12 (s, 1H), 5.08 (s, 2H), 3.77-3.62 (m, 1H), 3.21 (d, J=6 Hz, 2H) 2.99 (m, 1H), 2.77 (m, 2H).
IR(KBr): 3303, 3067, 1694, 1538, 1257, 741 cmxe2x88x921.
MS(FD) m/e 329.
Analysis for C32H45N3O4S: Calcd: C, 65.63; H, 5.81; N, 4.25; Found: C, 65.48; H, 5.82; N, 4.29.
F. [3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[3xe2x80x2-N-(benzyloxycarbonyl)amino-2xe2x80x2-hydroxy-4xe2x80x2-(phenyl)thiol]butyl decahydroisoquinoline-3-N-t-butyl carboxamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2F, using 6.3 g (19 mmol) of the subtitled compound of Preparation 8E, 5 g (21 mmol) of [3S -(3R*,4aR*,8aR*)]-decahydroisoquinoline-3-N-t-butylcarboxamide in 300 mL of ethanol to provide a residue. This residue was purified using flash chromatography (gradient eluent of 0-20% ethyl acetate in methylene chloride) to provide 4.3 g of a white solid.
Yield: 40%.
1H NMR (CDCl3): xcex4 7.41-7.11 (m, 10H), 5.90 (d, J=5 Hz, 1H), 5.64 (s, 1H), 5.05 (d, J=4 Hz, 2H), 4.08-3.90 (m, 2H), 3.40 (d, J=6, 2H), 3.05 (s, 1H), 2.95-2.85 (m, 1H), 2.62-2.45 (m, 2H), 2.28-2.15 (m, 2H), 2.05-1.88 (m, 2H), 1.78-1.10 (m, 7H), 1.29 (s, 9H).
IR (KBr) 3330, 2925, 2862, 1706, 1661, 1520, 1454, 1246, 738, 694 cmxe2x88x921.
MS(FD): m/e 568 (M+), 467.
Analysis for C32H45N3O4S: Calcd: C, 67.69; H, 7.99; N, 7.40; Found: C, 67.64; H, 8.20; N, 7.45.
G. [3S-(3R*,4aR*,8aR*,2xe2x80x2S*,3xe2x80x2S*)]-2-[3xe2x80x2-amino-2xe2x80x2-hydroxy-4xe2x80x2-(phenyl)thio]butyl decahydroisoquinoline-3-N-t-butyl carboxamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Procedure 2G using 1 g (1.8 mmol) of the subtitled compound of Preparation 8F and 40 mL of a 30% hydrobromic acid in acetic acid solution, with the exception that the crude material was dissolved in 30 mL of methanol. To the resulting solution, was added 2 mL of diethylamine and 2 mL of concentrated ammonium hydroxide and then the mixture was concentrated under reduced pressure to provide a residue. This residue was redissolved in water and ethyl acetate. The resulting layers were separated and the organic layer was washed sequentially with an aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide a residue. This residue was purified using flash chromatography (gradient eluent of 0-10% methanol in chloroform (containing 3 drops of ammonium hydroxide per 1000 mL of chloroform) to provide 0.54 g of a white foam.
Yield: 71%. separate
1H NMR (CDCl3): xcex4 7.41-7.16 (m, 5H), 6.07 (s, 1H), 3.78-3.70 (m, 1H), 3.45-3.38 (m, 1H), 3.03-2.84 (m, 3H), 2.38-2.20 (m, 3H), 2.00-1.05 (m, 12H), 1.33 (s, 9H).
IR (KBr): 2924, 2862, 1660, 1517, 1454, 1439, 737, 691 cmxe2x88x921.
MS(FD): m/e 434 (M+), 293.
Preparation 9
A. 3-Methoxy-N-phenylbenzamide
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1 M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid.
Yield: 95%.
B. 3-Methoxy-2-methyl-N-phenylbenzamide
To a cold (xe2x88x9270xc2x0 C.) solution of 4.54 g (20 mmol) of the subtitled compound of Preparation 9A and 5.11 g (44 mmol) of TMEDA in 70 mL of anhydrous tetrahydrofuran, was added 26.9 mL of a 1.56 M solution of n-butyl lithium in hexane. The resultant reaction mixture was warmed to xe2x88x9215xc2x0 C. and stirred for approximately 45 minutes to provide a yellow slurry. The slurry was then recooled to xe2x88x9270xc2x0 C. and 2.89 g (20 mmol) of methyl iodide was added, resulting in the formation of a white precipitate. The reaction mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride and diluted with diethylether. The resulting layers were separated and the organic phase washed sequentially with saturated ammonium chloride, water, saturated sodium bicarbonate and brine solutions. The organic extracts were then dried over sodium sulfate and concentrated to provide a white solid which was purified by recrystallization from a 2:1 ethyl acetate/hexane solution to provide 4.00 g of needles.
Yield: 99%.
1H NMR (CDCl3): xcex4 2.36 (s, 3H), 3.88 (s, 3H), 3.89 (s, 1H), 6.90-7.70 (m, 8H).
IR (CHCl3): 3424, 3013, 2963, 2943, 2840, 1678, 1597, 1585, 1519, 1463, 1438, 1383, 1321, 1264, 1240, 1178, 1083, 1069 cmxe2x88x921.
MS(FD): m/e 241 (M+, 100).
Analysis for C15H15NO2: Calcd: C, 74.67; H, 6.27; N, 5.80; Found: C, 74.65; H, 6.29; N, 5.82.
C. 3-Hydroxy-2-methylbenzoic acid
A mixture of 1.21 g (5.00 mmol) of the subtitled compound of Preparation 9B, 35 mL of 5N hydrochloric acid and 20 mL of a 30% solution of hydrobromic acid in acetic acid were heated at reflux for 24 hours. After cooling, the reaction mixture was diluted with 100 mL of ethyl acetate and 100 mL of water. The resulting layers were separated and the organic layer was washed once with water and then basified to pH 11 using 0.5N sodium hydroxide The resulting layers were separated and the aqueous layer reacidified to pH 1 using 5N hydrochloric acid. The desired compound was then extracted from this aqueous layer using ethyl acetate. The ethyl acetate extracts were then washed with brine, dried over sodium sulfate, filtered, and then concentrated to provide a residue which after two concentrations from hexane yielded 750 mg of a white solid.
Yield: 98%.
1H NMR (DMSO-d6): xcex4 2.26 (s, 3H), 6.98 (d, J=8.03 Hz, 1H), 7.02 (t, J=7.69 Hz, 1H), 7.15 (d, J=7.37 Hz, 1H), 9.55 (br.s, 1H).
IR (CHCl3): 3600-2100 (br.), 3602, 2983, 1696, 1588, 1462, 1406, 1338, 1279, 1174, 1154, 1075, 1038, 920, 892, 854, 816 cmxe2x88x921.
MS(FD): m/e 152 (M+, 100).
Analysis for C8H8O3: Calcd: C, 63.15; H, 5.30; Found: C, 63.18; H, 5.21.
Alternatively, the desired subtitled compound was prepared by adding 22.6 g (0.33 mol) of sodium nitrite in small portions to a cooled (xe2x88x9210xc2x0 C.) solution of 45 g (0.30 mol) of 3-amino-2-methylbenzoic acid and 106 g (58 mL; 1.08 mol) of concentrated sulfuric acid in 400 mL of water, while maintaining the temperature below 7xc2x0 C. The resultant reaction mixture was stirred for approximately 30 minutes at xe2x88x9210xc2x0 C., poured into a solution of 240 mL of concentrated sulfuric acid in 1.2 L water, and then slowly heated to 80xc2x0 C. (heavy gas evolution occurs between the temperatures of 40-60xc2x0 C.). When the gas evolution stopped, the reaction mixture was cooled to room temperature and the subtitled compound was extracted five times with ethyl acetate (600 mL). The combined organic phases were combined with 500 mL of an aqueous saturated sodium carbonate solution. The resultant layers were separated and the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid. The titled compound was then extracted using ethyl acetate (500 mL) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a crude material. This material was purified using two recrystallizations from a ethyl acetate/chloroform mixture to provide 23.2 g of a light orange powder.
Yield: 52%.
Preparation 10
A. 2-Ethyl-3-methoxy-N-phenylbenzamide
The subtitled compound was reared substantially in accordance with the procedure detailed in Preparation 9B, using 13.5 mL (21 mmol) of 1.56M n-butyl lithium, 2.27 g (10.0 mmol) of the subtitled compound of Preparation 9A, 2.56 g (22.0 mmol) of TMEDA and 1.56 g (10.0 mmol) of ethyl iodide in 50 mL of anhydrous tetrahydrofuran. The resultant crude material was purified by recrystallization from a 3:1 solution of ethyl acetate/hexane to provide 1.57 g of needles.
Yield: 62%.
1H NMR (CDCl3): xcex4 1.22 (t, J=7.4 Hz, 3H), 2.81 (q, J=7.4 Hz, 2H), 3.88 (s, 3H), 6.96 (d, J=8.2 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 7.10-7.45 (m, 4H), 7.50 (s, 1H), 7.62 (d, J=7.95 Hz, 1H).
MS(FD): m/e 255 (M+, 100).
Analysis for C16H17NO2: Calcd: C, 75.27; H, 6.71; N, 5.49; Found: C, 75.39; H, 6.72; N, 5.43.
B. 2-Ethyl-3-hydroxybenzoic Acid
A solution containing 180 mg (0.71 mmol) of the subtitled compound of Preparation 10A, 3 mL of 5N hydrochloric acid and 3 mL of a 30% solution of hydrobromic acid/acetic acid were heated for 20 hours in a sealed tube at 155xc2x0 C. After cooling, the reaction mixture was diluted with ethyl acetate and water. The resulting layers were separated and the organic layer was extracted once with water and then basified to pH 11 using 0.5N sodium hydroxide. The resulting layers were separated and the aqueous layer reacidified to pH 1 using 5N hydrochloric acid. The desired compound was then extracted from this aqueous layer using ethyl acetate. The ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and then concentrated to provide 103 mg of a pale red solid.
Yield: 88%.
1H NMR (acetone-d6): xcex4 1.16 (t, J=7.4 Hz, 3H), 2.98 (q, J=7.4 Hz, 2H), 7.00-7.15 (m, 2H), 7.32-7.36 (m, 1H), 8.48 (br.s, 1H).
MS(FD): m/e 166 (M+, 100).
Preparation 11
A. 2-Fluoro-3-methoxy-N-phenylbenzamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 9B, by adding a solution of 3.15 g (10.0 mmol) of N-fluorobenzenesulfonimide in 5 mL of tetrahydrofuran to a solution containing 13.5 mL (21.0 mmol) of 1.56M n-butyl lithium, 2.27 g (10.0 mmol) of the subtitled compound of Preparation 9A and 2.56 g (22.0 mmol) of TMEDA in 50 mL of anhydrous tetrahydrofuran. The resultant crude material was recrystallized twice from a 2:1 solution of ethyl acetate/hexane and then further purified using radial chromatography (6 mm, 0.5% ethyl acetate in methylene chloride) to provide 540 mg of an off-white solid.
Yield: 22%.
1H NMR (CDCl3): xcex4 3.94 (s, 3H), 7.05-7.80 (m, 8H), 8.35-8.50 (m, 1H).
MS(FD): m/e 245 (M+, 100).
B. 2-Fluoro-3-hydroxybenzoic Acid
The subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 9C, using a solution of 255 mg (1.02 mmol) of the subtitled compound of Preparation 11A, 3 mL of 5N hydrochloric acid and 5 mL of a 30% solution of hydrobromic acid in acetic acid to provide 134 mg of a white solid.
Yield: 86%.
1H NMR (acetone-d6): xcex4 7.05-7.50 (m, 5H).
MS(FD): m/e 156 (M+, 100).
Preparation 12
A. 4-N-(Phenyl)carbamoyl pyridine
A solution of 22.8 mL (250 mmol) of aniline in 104.5 mL (750 mmol) of triethylamine was slowly added to a solution of 44.5 g (250 mmol) of 4-chloroformyl pyridinium hydrochloride in 500 mL of chloroform. The resulting reaction mixture was stirred overnight and then refluxed for 2 hours. After cooling, the reaction mixture was diluted with 600 mL of water which resulted in the formation of a precipitate. After adding 200 mL of isopropanol to the mixture, the resultant layers were separated and the organic layer was washed sequentially with 0.1N sodium hydroxide, water and then brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure at 70xc2x0 C. to provide a white solid with a brown tinge. This solid was washed with 200 mL of ethyl acetate to provide 38.9 g of the desired subtitled compound.
Yield: 78%.
B. 4-N-(Phenyl)carbamoyl pyridine N-oxide
To a hot (85-90xc2x0 C.) solution of 19.8 g (100 mmol) of the subtitled compound of Preparation 12A in 60 mL of glacial acetic acid, was slowly added 51 mL of hydrogen peroxide behind a blast shield. The resultant reaction mixture was reacted for approximately four hours at 90xc2x0 C., cooled to room temperature, diluted in about 60 mL of a mixture of isopropanol and chloroform and then basified to pH 12. The resultant layers were separated and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a pale yellow solid. This solid was triturated with 250 mL of methylene chloride and reduced to dryness to provide 15.95 g of an off-white solid.
Yield: 75%.
C. 2-Chloro-4-N-(phenyl)carbamoyl pyridine
To a solution of 20.2 g (97.0 mmol) of phosphorus pentachloride in 27 mL (289 mmol) of phosphorous oxychloride, was added 14.4 g (67.2 mmol) of the subtitled compound of Preparation 12B. The resultant reaction mixture was slowly heated to 130xc2x0 C. and reacted for approximately 40 minutes. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to provide a residue. This residue was redissolved in 80 mL of water and then diluted with 80 mL of aqueous potassium carbonate resulting in the formation of a yellow precipitate. The precipitate was isolated by filtration, dissolved in 250 mL or hot ethanol and then hot filtered to provide a dark yellow solution. This solution was concentrated under reduced pressure to approximately 160 mL and then hot filtered again before the addition of about 50-60 mL of water. The resultant solution was cooled and the desired compound was isolated by recrystallization to provide 8.0 g of pale yellow and white needles.
Yield: 51%.
D. 2-Methoxy-4-N-(phenyl)carbamoyl pyridine
To a slurry of 4.09 g (18.0 mmol) of the subtitled compound of Preparation 12C in 30 mL of methanol, was added 2.92 g (42.0 mmol) of sodium methoxide. The resultant reaction mixture was refluxed for approximately eighteen hours, cooled and concentrated under reduced pressure to provide a solid. This solid was washed with water and triturated with cold benzene to provide 1.8 g of a solid. Analysis of this solid indicated that the reaction was not complete, so an additional 10.01 g (144 mmol) of sodium methoxide was added to the solid in methanol. The resultant reaction mixture was refluxed in methanol for fifteen hours and worked up identically to provide 300 mg of a solid. This solid was purified using column chromatography (2 mm plate, eluent of 40% ethyl acetate in hexane) followed by recrystallization from hot hexane to provide 140 mg of the desired compound.
Yield: 3%.
E. 2-Methoxy-3-methyl-4-N-(phenyl)carbamoyl pyridine
The subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 9B, using 260 mg (1.17 mmol) of the subtitled compound of Preparation 12D, 404 xcexcL (2.68 mmol) of TMEDA, 1.78 mL (2.68 mmol) of n-butyl lithium, and 329 xcexcL (5.61 mmol) of methyl iodide in 2 mL of tetrahydrofuran. The crude material was purified using radial chromatography (2 mm plate; eluent of 40% ethyl acetate in hexane) followed by recrystallization from hot hexane to provide 140 mg of the desired subtitled compound.
F. 3-methyl-2-pyridine-4-carboxylic acid
A slurry of 150 mg (0.598 mmol) of the subtitled compound of Preparation 12E in 4 mL of 5N hydrochloric acid (aqueous) was refluxed for approximately five hours. After cooling, the reaction mixture was concentrated under reduced pressure to provide a yellow oil. This oil was dissolved in 15 mL of water and the resultant solution was adjusted to pH 8 using potassium hydroxide and then diluted with 10 mL of toluene. The resulting layers were separated and the aqueous layer was acidified to pH 3.5 using a 5N hydrochloric acid solution and then concentrated under reduced pressure to provide a yellow solid. This solid was slurried in 2 mL of hot ethanol and filtered through a cotton plug. The filtrate was then reduced to dryness under reduced pressure to provide 130 mg of a solid. This solid was washed with 5 mL of hot 10% acetic acid in ethyl acetate to provide 17 mg of a solid which was then crystallized in ethanol to provide 6.8 mg of the desired subtitle compound.
Yield: 6%.
Preparation 13
2,6-Dichloro-3-hydroxy benzoic acid
Chlorine gas (20 g; 282 mmol) was slowly bubbled through a cold (xe2x88x9270xc2x0 C.) solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, resulting in a temperature increase to about xe2x88x925xc2x0 C. The reaction mixture was recooled and after approximately thirty minutes, the chlorine gas was flushed out with nitrogen. The reaction mixture was then warmed to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recrystallization from 90 mL of water followed by recrystallization from 250 mL of benzene containing 10 mL of acetone to provide 4.8 g of the desired titled compound.
Yield: 16%.
Preparation 14
2-Chloro-3-hydroxy benzoic acid
Chlorine gas (10.3 g; 147 mmol) was slowly bubbled through a cold solution of 20 g (145 mmol) of 3-hydroxy benzoic acid in 100 mL of methanol, under nitrogen, while maintaining the temperature below xe2x88x9260xc2x0 C. After approximately thirty minutes, the chlorine gas was flushed out with nitrogen and the reaction mixture was allowed to warm to room temperature and diluted with 100 mL of water. The desired titled compound was isolated by recrystallization to provide a white solid. This solid was purified by recrystallization from 50 mL of water followed by recrystallization from 130 mL of benzene containing 10 mL of acetone to provide the desired titled compound.
Preparation 15
A. 2Methyl-3-methoxy benzoate methyl ester
A slurry of 306 mg (2.00 mmol) of the subtitled compound of Preparation 9C, 1.06 mL (20.0 mmol) of methyl iodide and 1.38 g (10.0 mmol) of potassium carbonate in 8 mL of acetone was refluxed for approximately 3 hours. Since the reaction was not complete, an additional 2 mL (37.7 mmol) of methyl iodide, 2 g (14.5 mmol) of potassium carbonate and 10 mL of acetone were added to the reaction mixture. After refluxing the mixture for approximately sixteen hours, the mixture was filtered. The filtrate was then concentrated under reduced pressure to provide a residue. This residue was dissolved in ethyl acetate and washed with water and then reduced to dryness under reduced pressure to provide 188 mg of material which was 88% desired product.
B. 2-Methyl-3-methoxy benzoic acid
A solution of 116 mg (4.86 mmol) of lithium hydroxide in 1 mL of water was added to a solution of 175 mg (0.97 mmol) of the subtitled compound of Preparation 15A in 3 mL of tetrahydrofuran. The resultant reaction mixture was stirred rapidly. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated under reduced pressure to provide a residue. This residue was redissolved with 10 mL of hexane, 25 mL of water and 3 mL of 1N sodium hydroxide. The resulting layers were separated and the aqueous layer was diluted with ethyl acetate and then acidified to pH 1 using 1M hydrochloric acid. The resulting layers were separated and the ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and reduced to dryness under reduced pressure to provide 73 mg of the desired subtitled compound.
Preparation 16
A. 2-Butyl-3-methoxy-N-phenylbenzamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 9B, using 11.95 mL of 1.51M of n-butyl lithium in hexanes (18.04 mmol), 1.95 g (8.95 mmol) of the subtitled compound of Preparation 9A, 2.19 g (18.89 mmol) of TMEDA and 1.60 g (9.45 mmol) butyl iodide in 30 mL of anhydrous tetrahydrofuran. The resultant crude material was purified using radial chromatography (4 mm plate; eluent of 15% ethyl acetate in hexane) to provide 83 mg of a clear, colorless oil.
Yield: 3.5%.
1H NMR (CDCl3): xcex4 0.89 (t, J=7.27 Hz, 3H), 1.36 (m, 2H), 1.56 (m, 2H), 2.78 (m, 2H), 3.84 (s, 3H), 6.92 (d, J=7.98 Hz, 1H), 7.00 (d, J=7.36 Hz, 1H), 7.11-7.22 (m, 2H) 7.35 (t, 2H), 7.59 (m, 2H).
IR (CHCl3): 3691, 3619, 3424, 3024, 3010, 2963, 2874, 1679, 1602, 1380, 1517, 1459, 1437, 1315, 1265, 1177, 1055, 877 cmxe2x88x921.
MS(FD): m/e 283 (M+, 100).
B. 2-Butyl-3-hydroxybenzoic Acid
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 10B, using 80 mg (0.28 mmol) of the subtitled compound of Preparation 16A in 2 mL of 5N hydrochloric acid, and 2 mL of 30% hydrobromic acid in acetic acid to provide 44 mg of crude material which was used without further purification.
Yield: 60% (by 1H NMR).
1H NMR (CDCl3): xcex4 0.96 (t, J=8.09 Hz, 3H), 1.44 (m, 2H), 1.59 (m, 2H), 3.03 (m, 2H), 6.99 (d, j=8.03 Hz, 1H), 7.15 (t, J=7.77 Hz, 1H), 7.59 (d, J=6.85 Hz, 1H).
Preparation 17
A. 3-Methoxy-2-propyl-N-phenylbenzamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 9B, using 2.5 g (11.0 mmol) of the subtitled compound of Preparation 9A, 2.81 g (24.2 mmol) of TMEDA, 15.23 mL (23.13 mmol) of n-butyl lithium and 1.33 g (11.0 mmol) of allyl bromide in 30 mL of tetrahydrofuran to provide 2.5 g of crude material. This material was dissolved in 30 mL of absolute ethanol in the presence of 1.5 g of 10% palladium-on-carbon and the resulting mixture was reacted under a hydrogen atmosphere for approximately twelve hours. The mixture was then filtered over celite and the filtrate was concentrated under reduced pressure to provide an orange oil. This oil was purified using radial chromatography (6 mm plate; eluent of 10% ethyl acetate in hexane) to provide 438 mg of a white foam.
Yield: 15%
1H NMR (CDCl3): xcex4 0.94 (t, J=7.35 Hz, 3H), 1.62 (m, 2H), 2.75 (m, 2H), 3.84 (s, 3H), 6.92 (d, J=8.06 Hz, 1H), 7.00 (d, J=7.39 Hz, 1H), 7.16 (m, 2H), 7.34 (t, 2H), 7.59 (d, 2H), 7.69 (br.s, 1H).
B. 3-Hydroxy-2-propylbenzoic Acid
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 10B, using 438 mg (1.62 mmol) of the subtitled compound of Preparation 17A in 7 mL of 5N hydrochloric acid and 7 mL of 30% hydrobromic acid in acetic acid to provide a tan solid. This solid was purified by recrystallization from hot toluene to provide 84 mg of a tan solid.
Yield: 29%.
1H NMR (CDCl3): xcex4 1.01 (t, J=7.33 Hz, 3H), 1.63 (m, 2H), 2.98 (m, 2H), 6.98 (d, J=7.97 Hz, 1H), 7.14 (t, J=7.86 Hz, 1H), 7.57 (d, J=7.25 Hz, 1H).
IR (KBr): 3383, 3047, 2962, 2872, 2641, 1698, 1458, 1412, 1341, 1296, 1278, 1223, 1174, 1086, 929, 815, 752 cmxe2x88x921.
MS(FD) : m/e 180 (M+, 100)
Preparation 18
A. 2-Isopropyl-3-ethoxybenzonitrile
To a mixture of 2.76 g (0.115 mol) of magnesium in 75 mL of diethylether, was slowly added 24.31 g (0.143 mol) isopropyl iodide. The resulting reaction mixture was allowed to react until all of the magnesium was consumed. Then, a solution of 15.0 g (0.92 mol) of 2,3-dimethoxy benzonitrile in 75 mL of diethylether was added over ninety minutes. The resulting reaction mixture was reacted overnight at room temperature and then refluxed for four hours. The resultant reaction mixture was then cooled to 0xc2x0 C., and the top layer was decanted into saturated ammonium chloride and ice. The resultant layers were separated and the organic layer was washed sequentially with a dilute sodium hydroxide solution, water, and a dilute hydrochloric acid solution, dried over sodium sulfate, filtered and then concentrated to provide an orange oil. This oil was distilled under reduced pressure (5 inch vigreux column; 0.2 mm Hg) to provide 6.25 g, of an orange oil.
Yield: 39%.
1H NMR (CDCl3): xcex4 1.37 (d, J=6.47 Hz, 6H), 3.55 (m, 1H), 3.83 (s, 3H), 7.04 (d, J=7.79 Hz, 1H), 7.18 (m, 2H).
IR (CHCl3): 3690, 3617, 3019, 2968, 2939, 2841, 2228, 1577, 1470, 1457, 1440, 1387, 1363, 1265, 1100, 1070, 1045, 878 cmxe2x88x921.
MS(FD): m/e 175 (M+, 100).
B. 3-Hydroxy-2-isopropyl benzoic acid
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 10B, using 330 mg (1.88 mmol) of the subtitled compound of Preparation 18A in 2 mL of 5N hydrochloric acid and 30% hydrobromic acid in acetic acid. The crude product was purified using radial chromatography (2 mm plate; eluent of 3% methanol in methylene chloride containing 1% acetic acid) to provide 125 mg of a rose colored solid.
Yield: 37%.
1H NMR (CDCl3): xcex4 1.40 (d, J=6.92 Hz, 6H), 3.62 (m, 1H), 6.83 (d, J=7.86 Hz, 1H), 7.06 (t, J=7.89 Hz, 1H), 7.24 (d, J=7.55 Hz, 1H).
IR (CHCl3): 3599, 3025, 2965, 2876, 1695, 1603, 1584, 1466, 1454, 1404, 1360, 1275, 1234, 1166, 1148, 1086, 1057, 926 cmxe2x88x921.
MS(FD): m/e 180 (M+, 100).
Analysis for C10H12O3: Calcd: C, 66.65; H, 6.71; Found: C, 66.53; H, 6.84.
Preparation 19
3-methylisonicotinic acid
To a hot (155xc2x0 C.) solution of 10.7 g (0.1 mol) of 3,4-lutidine in 100 mL diphenylether, was added 18 g (0.16 mol) selenium dioxide in portions. After about 20 minutes, the reaction was heated to 185xc2x0 C. and allowed to react for approximately thirty minutes. After cooling, the reaction mixture was diluted with water and filtered. The filtrate was extracted with chloroform and the chloroform extracts were then concentrated under reduced pressure to provide 6.0 g of a pale brown solid.
Yield: 44%.
1H NMR (CDCl3): xcex4 2.43 (s, 3H), 7.61 (d, J=4.98 Hz, 1H), 8.49 (d, J=4.99 Hz, 1H), 8.53 (s, 1H).
13C NMR (CDCl3): xcex4 17.91, 123.21, 132.81, 138.15, 148.12, 152.71, 167.89 ppm.
IR (KBr): 3425, 2418, 1724, 1606, 1445, 1387, 1303, 1278, 1235, 1100, 1272, 850 cmxe2x88x921.
MS(D): m/e 138 (M+, 100).
Preparation 20
5-quinolinecarboxylic acid
To a solution containing 15 g (0.1 mol) of m-aminobenzoic acid, 27 g (0.13 mol) of m-nitrobenzene sulfonate and 25 g (0.4 mol) of glycerol, was added 125 g of 70% sulfuric acid. The resultant reaction mixture was refluxed for about 2.5 hours, diluted with 125 mL of water, basified to pH 9 using ammonium hydroxide, stirred overnight with 5 g of charcoal, and then filtered. The filtrate was then boiled with 5 g charcoal, filtered, and then cooled to 50xc2x0 C., acidified to pH 5 with glacial acetic acid (15 mL), and filtered to provide a brown solid. This solid was boiled in 300 mL of water containing 10 mL of acetic acid and hot filtered to provide crude material. This material was purified using recrystallization from boiling acetic acid to provide 6.1 g of a pale brown solid.
Yield: 32%.
1H NMR (CDCl3): xcex4 7.62 (m, 1H), 7.81 (t, J=7.82 Hz, 1H), 8.20 (m, 2H) , 8.93 (d, =3.79 Hz, 1H), 9.24 (d, J=8.58 Hz, 1H).
IR (KBr): 2772, 2431, 1906, 1708, 1610, 1589, 1507, 1363, 1323, 1269, 1235, 1211, 1141, 1076, 1034, 999, 866, 807 cmxe2x88x921.
MS(FD): m/e 173 (M+, 100).
Preparation 21
1,2,3,4-tetrahydro-5-quinolinecarboxylic acid
A solution containing 1.03 g (5.95 mmol) of the titled compound of Preparation 20, 1.87 g (29.77 mmol) of ammonium formate in 100 mL of ethanol was purged with nitrogen for 10 minutes. To this solution was added 0.5 g of palladium black and the resultant reaction mixture was heated to 65xc2x0 C. After approximately three hours, the reaction mixture was filtered; the resultant filtrate was concentrated under reduced pressure to provide a residue. This residue was partitioned between water (pH 4) and a solution of 10% isopropanol in chloroform. The resulting layers were separated, and the organic layer was washed with water (pH=4), dried over sodium sulfate, filtered, and concentrated to provide crude material. This material was purified using radial chromatography (2 mm plate; gradient eluent of 5-10% methanol in methylene chloride containing 1% acetic acid) to provide 87 mg of a tan solid.
Yield: 8%.
1H NMR (CDCl3): xcex4 1.04 (m, 2H) , 2.16 (t, 2H), 2.40 (m, 2H), 5.81 (d, J=8.05 Hz, 1H), 6.09 (t, J=7.78 Hz, 1H), 6.23 (d, J=7.96 Hz, 1H).
IR(KBr): 3296, 2965, 2929, 1691, 1597, 1474, 1461, 1443, 1350, 1305, 1279, 1236, 1184, 1159, 1106, 1073, 1022, 827 cmxe2x88x921.
MS(FD): m/e 177 (M+, 100).
Analysis for C10H11NO2: Calcd: C, 67.78; H, 6.26; N, 7.90; Found: C, 67.96; H, 6.10; N, 7.88.
Preparation 22
A. 3-Amino-2-methyl benzoate methyl ester
A solution of 10 g (66.2 mmol) of 3-amino-2-methyl benzoic acid and 20 g of p-toluenesulfonic acid monohydrate in 400 mL of methanol was refluxed overnight and then diluted with a mixture of ethyl acetate and 1M potassium carbonate. The resulting layers were cooled and then separated. The organic layer was then washed sequentially with 1M potassium carbonate, and brine, dried over sodium sulfate, filtered and then concentrated to provide 9.23 g of an orange oil.
Yield: 85%.
1H NMR (CDCl3): xcex4 2.34 (s, 3H), 3.73 (br.s, 2.H), 3.88 (s, 3H), 6.81 (d, J=7. 96 Hz, 1H), 7.05 (t, J=7.78 Hz, 1H), 7.19-7.30 (m, 1H).
IR (CHCl3): 3406, 3027, 3012, 2973, 2953, 1718, 1621, 1467, 1435, 1315, 1301, 1265, 1196, 1159, 1108, 1066, 1045, 810 cmxe2x88x921.
MS(FD): m/e 165 (M+, 100).
B. 3-N-(Methylsulfonyl)amino-2-methyl benzoate methyl ester
To a cold (0xc2x0 C.) solution of 1.07 g (6.48 mmol) of the subtitled compound of Preparation 22A in 50 mL of anhydrous methylene chloride, was added 1.18 g (6.80 mmol) of methylsulfonic anhydride. The resultant reaction mixture was reacted overnight at room temperature and then diluted with 100 mL of methylene chloride, washed twice with a sodium bicarbonate solution, dried over sodium sulfate, filtered, concentrated, redissolved in hexane and then concentrated again to provide a residue. This residue was then triturated three times in hexane and then reduced to dryness under reduced pressure to provide 1.46 g of a pink solid. This solid was then recrystallized using 20 mL of a 30% hexane/50% ethyl acetate/20% methanol mixture.
Yield: 57%.
1H NMR (DMSO-d6): xcex4 2.25-2.45 (m, 4.5H), 2.97 (s, 1.5H), 3.80 (s, 3H), 7.23-7.63 (m, 3H), 9.24 (s, 1H).
IR (KBr): 3900-2400 (br.), 3298, 1713, 1466. 1320, 1290, 1265, 1248, 1210, 1183, 1156, 1047, 971, 964, 752, 563, 519 cmxe2x88x921.
MS(FD): m/e 243 (M+, 100).
Analysis for C10H13NO4S: Calcd: C, 49.37; H, 5.39; N, 5.76; Found: C, 49.15; H, 5.54; N, 5.80.
C. 3-N-(Methylsulfonyl)amino-2-methyl benzoic acid
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 15B, using 400 mg (1.64 mmol) of the subtitled compound of Preparation 22B, and 118 mg (4.93 mmol) of lithium hydroxide in 20 mL of tetrahydrofuran and 8 mL of water, to provide 206 mg of a white solid.
Yield: 55%.
1H NMR (DMSO-d6): xcex4 2.43 (s, 3H), 2.97 (s, 3H), 7.26 (t, J=7.87 Hz, 1H), 7.43 (d, J=7.79 Hz, 1H), 7.60 (d, J=7.17 Hz, 1H).
IR (KBr): 3800-2200 (br.), 3252, 1685, 1404, 1334, 1309, 1277, 1149, 982, 965, 914, 780, 763, 748, 632, 518, 498 cmxe2x88x921.
MS(FD): m/e 243 (M+, 100).
A. 3-methoxy-N-phenylbenzamide
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid.
Yield: 95%.
B. 3-Methoxy-2-methyl-N-phenylbenzamide
To a cold (xe2x88x9270xc2x0 C.) solution of 4.54 g (20 mmol) of the subtitled compound of Preparation 23A and 5.11 g (44 mmol) of TMEDA in 70 mL of anhydrous tetrahydrofuran, was added 26.9 mL of a 1.56M solution of n-butyl lithium in hexane. The resultant reaction mixture was warmed to 15xc2x0 C. and stirred for approximately 45 minutes to provide a yellow slurry. The slurry was then recooled to xe2x88x9270xc2x0 C. and 2.89 g (20 mmol) of methyl iodide was added, resulting in the formation of a white precipitate. The reaction mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride and diluted with diethylether. The resulting layers were separated and the organic phase washed sequentially with saturated ammonium chloride, water, saturated sodium bicarbonate and brine solutions. The organic extracts were then dried over sodium sulfate and concentrated to provide a white solid which was purified by recrystallation from a 2:1 ethyl acetate/hexane solution to provide 4.00 g of needles.
Yield: 99%.
1H NMR (CDCl3): xcex4 2.36 (s, 3H), 3.88 (s, 3H), 3.99 (s, 1H), 6.90-7.70 (m, 8H).
IR (CHCl3): 3424, 3013, 2963, 2943, 2840, 1678, 1597, 1585, 1519, 1463, 1438, 1383, 1321, 1264, 1240, 1178, 1083, 1069 cmxe2x88x921.
MS(FD): m/e 241 (M+, 100).
Analysis for C15H15NO2: Calcd: C, 74.67; H, 6.27; N, 5.80; Found: C, 74.65; H, 6.29; N, 5.82.
C. 2-Methyl-3-hydroxybenzoic acid
A mixture of 1.21 g (5.00 mmol) of the subtitled compound of Preparation 23B, 35 mL of 5N hydrochloric acid and 20 mL of a 30% solution of hydobromic acid in acetic acid were heated at reflux or 24 hours. After cooling, the reaction mixture was diluted with 100 mL of ethyl acetate and 100 mL of water. The resulting layers were separated and the organic layer was washed once with water and then basified to pH 11 using 0.5N sodium hydroxide The resulting layers were separated and the aqueous layer reacidified to pH 1 using 5N hydrochloric acid. The desired compound was then extracted from this aqueous layer using ethyl acetate. The ethyl acetate extracts were then washed with brine, dried over sodium sulfate, filtered, and then concentrated to provide a residue which after two concentrations from hexane yielded 750 mg of a white solid.
Yield: 98%.
1H NMR (DMSO-d6): xcex4 2.26 (s, 3), 6.98 (d, J=8.03 Hz, 1H), 7.02 (t, J=7.69 Hz, 1H), 7.15 (d, J=7.37 Hz, 1H), 9.55 (br.s, 1H).
IR (CHCl3): 3600-2100 (br.), 3602, 2983, 1696, 1588, 1462, 1406, 1338, 1279, 1174, 1154, 1075, 1038, 920, 892, 854, 816 cmxe2x88x921.
MS(FD): m/e 152 (M+, 100).
Analysis for C8H8O3: Calcd: C, 63.15; H, 5.30; Found: C, 63.18; H, 5.21.
Alternative Preparation for 2-Methyl-3-hydroxybenzoic acid
To a cold (0xc2x0 C.) suspension of 0.54 g (3.3 mmol) of 2-methyl-3-aminobenzoic acid in 5 mL of water containing 0.65 mL of concentrated sulfuric acid, was added 0.25 g (3.6 mmol) of solid sodium nitrite. After approximately 15 minutes the reaction mixture was poured into 20 mL of warm water containing 4 mL of concentrated sulfuric acid. The resultant reaction mixture was heated slowly to 90xc2x0 C., resulting in gas evolution. After the gas evolution ceased, the solution was cooled to room temperature and extracted with ethyl acetate. The organic layers were combined, washed with 0.5N hydrochloric acid, dried and concentrated under reduced pressure. The crude residue was purified by rapid filtration through silica gel (eluent of 5% methanol in methylate chloride) to yield 350 mg of a white solid (m.p. 137-138xc2x0 C.).
Yield: 69%.
1H NMR (CDCl3): xcex4 8.18 (br.s, 1), 7.42 (d, J=7.7 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 2.46 (s, 3H).
Analysis for C8H8O3: Calcd: C, 63.15, H, 5.29; Found: C, 63.32; H, 5.36.
Preparation 24
A. N-(t-Butyl)-2-methylbenzamide
To a cold (0xc2x0 C.) solution of 139.2 g (0.9 mol) of o-toluoyl chloride in 1200 mL of methylene chloride at 25xc2x0 C., under nitrogen, was slowly added 180.0 g (1.8 mol) of triethylamine followed by the dropwise addition of a solution containing 73.14 g (1.0 mol) of t-butylamine in 200 mL of methylene chloride. The resulting reaction mixture was warmed to room temperature and allowed to react for 2.5 hours. The reaction mixture was then diluted with 1800 mL of water. The resulting organic and aqueous layers were separated, and the organic layer was washed sequentially with 2N sodium hydroxide, 1.0N hydrochloric acid and brine, dried over magnesium sulfate, filtered and then reduced to dryness under reduced pressure to provide 167.6 g of the desired subtitled compound as an offwhite solid (mp 77-78xc2x0 C.).
Yield: 97%.
1NMR (CDCl3): xcex4 1.41 (s, 9H), 2.41 (s 3H), 5.54 (br.s, 1H), 7.13-7.30 (m, 4H).
IR (CDCl3) 3430, 3011, 2971, 2932, 1661, 1510, 1484, 1452, 1393, 1366, 1304, 1216, 876 cmxe2x88x921.
MS(FD): m/e 191 (M+), 191 (100).
Analysis for C12 H7NO: Calcd: C, 75.35; H, 8.76; N, 7.32; Found: C, 75.10; H, 9.11; N, 7.20.
B. S-N-t-Butyl-2-(3-(N-benzyloxycarbonyl)amino-2-oxo-4-phenylbutyl)benzamide
To a solution of 7.0 g (36.5 mmol) of the subtitled compound of Preparation 24A in 200 mL of anhydrous tetrahydrofuran, was added 12.1 mL (80.3 mmol) of N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine (TMEDA) was added via syringe. The resulting solution was cooled to xe2x88x9278xc2x0 C. and then 55.9 mL of sec-butyllithium was added dropwise via syringe while maintaining the temperature of the reaction under xe2x88x9260xc2x0 C. The resulting reaction solution was then allowed to stir for approximately 1 hour at xe2x88x9278xc2x0 C. before the addition of a solution containing 5.00 g (14.6 mmol) of S-N-methoxy-N-methyl-2-(N-benzyloxycarbonyl)amino-3-phenylpropanamide in 50 mL of anhydrous tetrahydrofuran was added via cannula while maintaining the reaction temperature below xe2x88x9265xc2x0 C. The resulting reaction mixture was warmed to xe2x88x9220xc2x0 C., quenched using 20 mL of saturated ammonium chloride and then diluted with 200 mL of diethylether The organic and aqueous layers were separated and the organic layer was washed sequentially with water, 0.2N sodiumhydrogensulfate and brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide a colorless oil. This oil was purified using flash chromatography (eluent of 25% ethyl acetate in methylene chloride) to provide 6.08 g of a colorless foam.
Yield: 88%.
[xcex1]D xe2x88x92289.26xc2x0 (c 0.12, MeOH).
1H NMR (CDCl3) xcex4 1.38 (s, 9H), 2.99 (dd, J=15; 6 Hz, 1H), 3.24 (dd, J=15; 6 Hz, 1H), 3.99 (d, J=18 Hz, 1H), 4.16 (d, J=18 Hz, 1H), 4.72 (dd, J=15, 6 Hz, 1H), 5.00-5.09 (m, 2H), 5.56 (d, J=6 Hz, 1H), 5.93 (br.s, 1H), 7.03-7.40 (m, 14H).
IR (CHCl3): 3431, 3027, 3012, 2973, 1713, 1658, 1511, 1454, 1383, 1366, 1307, 1231, 1046 cmxe2x88x921.
MS(FD) m/e 472 (M+), 218 (100).
Analysis for C29 32N2O4: Calcd: C, 73.70; H, 6.82; N, 5.93; Found: C, 73.41; H, 6.98; N, 5.83.
C. [2R-(2R*,3S*)]-N-t-Butyl-2-(3-(N-benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutyl)benzamide
To a solution of 6.96 g (14.7 mmol) of the subtitled compound of Preparation 24B in 200 mL of absolute ethanol, under nitrogen, was added 2.78 g (73.5 mmol) of sodium borohydride. When the reaction was substantially complete, as indicated by thin layer chromatography (TLC), the reaction mixture was diluted with 200 mL of ethyl acetate and quenched by the dropwise addition of 20 mL of saturated ammonium chloride. The organic and aqueous layers were then separated and the organic layer was washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 6.4 g of a colorless oil. This oil was purified using flash chromatography (gradient eluent of 2-10% methylene chloride in ethyl acetate) to provide 5.12 g the subtitled compound.
Yield74%.
[xcex1]D xe2x88x9210.38xc2x0 (c, 0.10, MeOH).
1H NMR (CDCl3): xcex4 1.40 (s, 9H), 2.79 (dd, J=12; 3 Hz, 1H), 2.90-2.98 (m, 2H), 3.04 (44, J=12, 3 Hz, 1H); 3.70-3.81 (m, 1H), 3.97 (m, 1H), 4.96-5.08 (m, 2H), 5.10 (d, J=9 Hz, 1H), 5.88 (d, J=6 Hz, 1H), 5.93 (s, 1H), 7.13-7.42 (m, 14H).
IR (CHCl3): 3431, 3028, 3012, 2971, 1773, 1643, 1515, 1454, 1367, 1229, 1028 cmxe2x88x921.
MS(FD): m/e 475 (M+), 475 (100).
Analysis for C29H34 N2O4: Calcd: C, 73.39; H, 7.22; N, 5.99; Found: C, 73.12; H, 7.48; N, 5.62.
D. [2R-(2R*,3S*)]-N-t-Butyl-2-(3-amino-2-hydroxy-4-phenylbutyl) benzamide
A suspension was prepared containing 41.0 g (120 mmol) of the subtitled compound of Preparation 24C and 500 mg of 10% palladium-on-carbon in 150 mL of absolute ethanol. This suspension was shaken under 60 psi hydrogen in a Parr shaker apparatus. The 10% palladium-on-carbon catalyst was then removed by filtration. The resultant filtrate was reduced to dryness under reduced pressure to provide 31.1 g of a light yellow foam. This compound was used without further purification.
Yield: 96%.
[xcex1]D +34.68xc2x0 (c 1.0, MeOH).
1H NMR (CDCl3): xcex4 1.46 (s, 9H), 2.71 (dd, J=13.7; 9.5 Hz, 1H), 2.84 (dd, J=13.3; 2.51 Hz, 1H), 2.95-3.06 (m, 2H), 3.23-3.29 (m, 1H), 3.84-3.90 (m, 1H), 6.23 (s, 1H), 7.19-7.37 (m, 12H).
IR (CHCl3): 3440, 3382, 3007, 2970, 2934, 1643, 1516, 1454, 1367, 1213 cmxe2x88x921.
MS(FD): m/e 341 (M+), 341 (100).
Preparation 25
A. 2R-2-N(t-Butoxycarbonyl)amino-3-naphth-2-ylthio propanoic acid
To a solution of 2.14 g (13.4 mmol) 2-naphthalene thiol in 40 mL of anhydrous tetrahydrofuran at room temperature, was added a suspension of 0.54 g (13.5 mmol) of sodium hydride in mineral oil. After approximately 15 minutes, a solution of 2.5 g (13.4 mmol) of S-N(t-butoxycarbonyl)-serine-xcex2-lactone in 30 mL of tetrahydrofuran was added dropwise. The resultant reaction mixture was allowed to react for approximately one hour and then was concentrated under reduced pressure to provide a gummy solid. This solid was purified using flash chromatography (eluent of 1% methanol in ethyl acetate) to provide 4.35 g of a white solid.
Yield: 94%.
1H NMR (CDCl3): xcex4 10.25 (s, 1H), 7.89 (s, 1H), 7.78 (m, 3H), 7.46 (m, 3H), 5.39 (d, 1H), 4.61 (m, 1H), 3.49 (m, 2H), 1.37 (s, 9H).
B. 2R-N(Methoxy)-N(methyl) [2-N(t-butoxycarbonyl)amino-3-naphth-2-ylthio]propanamide
To a cold (0xc2x0 C.) solution containing 4.3 g (12.4 mmol) of the subtitled intermediate of Preparation 25A, 1.58 g (16.15 mmol) of N,O-dimethylhydroxylamine hydrochloride, 2.18 g (16.15 mmol) of 1-hydroxybenzotriazole hydrate (HOBTxc2x7H2O), 2.24 mL (16.15 mmol) of triethylamine and 2.73 mL (24.86 mmol) N-methylmorpholine in 100 mL of methylene chloride, was added 2.62 g (13.67 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The resulting reaction mixture was allowed to react at room temperature overnight. The reaction mixture was diluted with 100 mL of hexane, washed sequentially with 200 mL of a saturated sodium bicarbonate solution and 200 mL of brine. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a clear yellow oil.
1H NMR (CDCl3): xcex4 7.90 (s, 1H), 7.80 (m, 3H), 7.49 (m, 3H), 5.41 (d, 1H), 4.92 (m, 1H), 3.59 (s, 3H), 3.18-3.46 (m, 2H), 3.05 (s, 3H), 1.42 (s, 9H).
MS(FD): m/e 391 (M+), 390 (100).
C. 3R-N(t-Butyl)-2-[2xe2x80x2-oxo-3xe2x80x2-N(t-butoxycabonyl)amino-4xe2x80x2-naphth-2-ylthio]butyl benzamide
To a cold (xe2x88x9278xc2x0 C.) solution containing 8.60 g (45 mmol) of the subtitled compound of Preparation 24A, and 14.2 mL (95 mmol) of TMEDA in 100 mL of anhydrous tetrahydrofuran and under an inert atmosphere, was slowly added 111 mL (95 mmol) of a 0.85M solution of sec-butyllithium in hexanes, via syringe. The internal temperature of the reaction vessel was monitored during the addition of the sec-butyllithium to ensure that the temperature did not exceed xe2x88x9257xc2x0 C. After allowing the resultant reaction mixture to react for approximately one hour at xe2x88x9278xc2x0 C., a solution of 7.90 g (20 mmol) of the subtitled intermediate of Preparation 2B in 80 mL of tetrahydrofuran was added dropwise. When the addition was complete, the reaction was warmed to xe2x88x9220xc2x0 C. and then was quenched by the addition of a saturated ammonium chloride solution. The resulting mixture was then diluted with 600 mL of diethylether. The resulting layers were separated and the organic layer was washed sequentially with a 1M sodium bisulfate solution and a brine solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a yellow oil. This oil was purified using flash chromatography (gradient eluent of 10-50% ethyl acetate in hexane) to provide 8.5 g of the desired subtitled intermediate.
Yield: (82%).
1H NMR (CDCl3): xcex4 7.90 (s, 1H), 7.79 (t, 3H), 7.48 (m, 3H), 7.40 (d, 1H), 7.29 (m, 2H), 7.05 (d, 1H), 5.94 (br.s, 1H), 5.65 (m, 1H), 4.65 (d, 1H), 4.24 (d, J=17 Hz, 1H), 3.86 (d, J=17 Hz, 1H), 3.66 (m, 1H), 3.40 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H).
MS(FD): m/e 521 (M+), 521(100).
D. [(2R-(2R*,3R*)]-N(t-Butyl)-2-[2xe2x80x2-hydroxy-3xe2x80x2-N(t-butoxycarbonyl)amino-4xe2x80x2-naphth-2-ylthio]butyl benzamide
To a solution of 3.49 g (6.7 mmol) of the subtitled intermediate of Preparation 25C in 150 mL of absolute ethanol, was added 0.51 g (13 mmol) of sodium borohydride and the resulting reaction mixture was allowed to react overnight at room temperature. The reaction was then cooled to 0xc2x0 C., quenched with a saturated ammonium chloride solution and diluted with 550 mL of methylene chloride. The resulting layers were separated and the organic layer was washed sequentially with 1N hydrochloric acid, 2N sodium hydroxide and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a colorless foam. This foam was purified using flash chromatography (gradient eluent of 10-25% hexane in ethyl acetate) to provide 2.78 g of the desired subtitled intermediate.
Yield: 78%.
1H NMR (CDCl3): xcex4 7.84 (5, 1H), 7.73 (m, 3H), 7.41 (m, 3H), 7.29 (t, 2H), 7.16 (t, 2H), 6.53 (s, 1H), 5.32 (d, 1H), 3.36 (m, 2H), 3.33 (m, 2H), 2.83 (m, 2H), 1.40 (s, 9H).
MS(FD): m/e 523 (M+), 522 (100).
Analysis for C30 H38N2O4S: Calcd: C, 68.94; H, 7.33; N, 5.36; Found: C, 68.65; H, 7.34; N, 5.15.
E. [(2R-(2R*,3R*)]-N(t-Butyl)-2-(2xe2x80x2-hydroxy-3xe2x80x2-amino-4xe2x80x2-naphth-2-ylthio]butyl benzamide
To a cold (0xc2x0 C.) solution of 2.89 g (5.53 mmol) of the subtitled intermediate of Preparation 25D in 100 mL of methylene chloride, was added 18 mL of trifluoroacetic acid. The resulting reaction mixture was allowed to react for approximately one hour. The reaction mixture was then concentrated under reduced pressure to provide a foam. This foam was slurried in toluene and then concentrated under reduced pressure to provide a foam which was purified using flash chromatography (eluent of 5% methanol in methylene chloride) to provide 1.71 g of a white foam.
Yield: 74%.
1H NMR (CDCl3): xcex4 7.75-7.85 (m, 4H), 7.24-7.51 (m, 7H), 6.06 (s, 1H), 3.75 (m, 1H), 3.61 (m, 1H), 3.07 (m, 2H), 2.95 (m, 2H), 1.47 (s, 9H).
MS(FD): m/e 423(M+), 422 (100).
Preparation 26
A. N-t-Butyl-2-methyl-1-naphthylamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 24A. The crude material was purified by recrystallization from a hexane/ethyl acetate mixture to provide 20.99 g of colorless needles (mp 124-126xc2x0 C.).
Yield: 68%.
1H NMR (CDCl3): xcex4 1.54 (s, 9H), 2.50 (s, 3H), 5.50-5.65 (br.s, 1H), 7.23-7.54 (m, 3H), 7.74 (d, J=10 Hz, 1H), 7.78 (d, J=10 Hz, 1H), 7.87 (d, J=10 Hz, 1H).
IR (CHCl3): 3424, 3010, 2969, 1660, 1512, 1503, 1454, 1366, 1291, 1263, 1221 cmxe2x88x921.
MS(FD) : m/e 241 (M+), 241 (100).
Analysis for C16H19NO: Calcd: C, 79.63; H, 7.94; N, 5.80; Found: C, 79.90; H, 8.11; N, 5.76.
B. S-N-t-Butyl-2-(3-(N-benzyloxycarbonyl)amino-4-phenyl-2-oxobutyl)-1-naphthylamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 24A. The resultant residue was purified using flash chromatography (gradient eluent of 10-30% ethyl acetate in hexane) to provide 7.43 g of a colorless foam.
Yield: 86%.
[xcex1]D xe2x88x926.86xc2x0 (c 0.10, MeOH).
1H NMR (CDCl3): xcex4 1.45 (s, 9H) , 3.03 (dd, J=15, 8 Hz, 1H), 3.18 (dd, J=15, 5 Hz, 1H), 3.91 (d, J=16 Hz, 1H), 4.04 (d, J=16 Hz, 1H), 4.70-4.80 (m, 1H), 4.94-5.06 (m, 2H), 5.41 (d, J=8 Hz, 1H), 6.12-6.20 (br.s, 1H), 7.10-7.38 (m, 11H), 7.42-7.58 (m, 2H), 7.76-7.85 (m, 2H), 7.93 (s, J=9 Hz, 1H).
IR (CHCl3): 3420, 3029, 3012, 2970, 1713, 1658 1505, 1455, 1367, 1232, 1045 cmxe2x88x921.
MS(FD): m/e 522 (M+), 522 (100).
Analysis for C33H34N2O4: Calcd: C, 75.84; H, 6.56; N, 5.36; Found: C, 75.56; H, 6.74; N, 5.17.
C. [2R-(2R*,3S*)]-N-t-Butyl-2-(3-(N-benzyloxycarbonyl)amino-3-phenylmethyl-2-hydroxypropyl)-1-naphthylamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 24C. The resultant material was purified using flash chromatography (gradient eluent of 2-10% ethyl acetate in methylene chloride) to provide 5.50 g of a colorless foam.
Yield: 74%.
[xcex1]D +11.85xc2x0 (c 0.20, MeOH).
1H NMR (CDCl3): xcex4 1.54 (s, 9H), 2.85-3.15 (m, 4H), 3.85-3.95 (m, 1H), 4.00-4.13 (m, 2H), 4.90-5.34 (m, 3H), 5.85-5.95 (m, 1H), 7.05-7.60 (m, 1H), 7.81 (d, J=9 Hz, 2H), 7.91 (d, 9 Hz, 2H).
IR (CHCl3): 3420, 3012, 2970, 1713, 1643, 1515, 1454, 1367, 1219, 1209, 1028 cmxe2x88x921.
MS(FD): m/e 524 (M+), 524 (100).
Analysis for C33H36N2O4: Calcd: C, 75.55; H, 5.92; N, 5.34; Found: C, 75.41; H, 7.16; N, 5.14.
D. [2R-(2R*,3S*)]-N-t-Butyl-2-(3-amino-2-hydroxypropyl)-1-naphthylamide
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 24D. The crude filtrate was concentrated to provide 1.30 g of a colorless foam which was used without any further purification.
Yield: 92%.
Preparation 27
A. 2-Iodo-4-hydroxymethyl toluene
To a solution of 5.0 g (19.1 mmol) of 2-iodo-3-methyl benzoic acid in 50 mL of anhydrous tetrahydrofuran, was slowly added 22 mL of a 1M borane solution in tetrahydrofuran. The resultant reaction mixture was reacted for approximately ninety minutes and then was quenched with ethanol resulting in the evolution of hydrogen gas. The mixture was diluted with ethyl acetate. The resulting layers were separated and the organic layer was washed sequentially with sodium bicarbonate and brine, dried over sodium sulfate, filtered and crystallized from a hexane/ethyl acetate mixture to provide 120 mg of the desired subtitled compound.
B. 2-Methyl-5-hydroxymnethyl benzoic acid
A mixture of 142 mg (5.92 mmol) of lithium hydroxide and 249 mg (1.48 mmol) of the subtitled compound of Preparation 27A in a 3:1 tetrahydrofuran/water mixture were reacted for approximately twenty four hours. When the reaction was complete, as indicated by TLC, the reaction mixture was concentrated under reduced pressure and acidified by the addition of 1N hydrochloric acid. The mixture was diluted with ethyl acetate and the resulting layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and reduced to dryness to provide 70 mg of the desired subtitled compound.
Preparation 28
2-Methyl-3-methylamino benzoic acid
To a solution of 500 mg (2.5 mmol) of 2-methyl-3-amino benzoate methyl ester in 5 mL of dimethylformamide, was added 387 mg (2.7 mmol) of methyl iodide and 700 mg (5.4 mmol) of diisopropylethylamine. The resultant reaction mixture was heated to 70xc2x0 C. for approximately two hours and then poured into 10 mL of 1N potassium hydroxide. After about sixteen hours, the mixture was acidified to pH 6 by the addition of 2N hydrochloric acid. The desired titled compound was extracted into ethyl acetate, dried and reduced to dryness under reduced pressure to provide 343 mg of a white solid (m.p. 165-167xc2x0 C.).
Yield: 84%.
1H NMR (CDCl3): xcex4 12.52 (br.s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 2.92 (s, 3H), 2.21 (s, 3H).
Analysis for C9H11NO2: Calcd: C, 65.44; H, 6.71; N, 8.48; Found: C, 65.62; H, 6.84; N, 8.26.
Preparation 29
A. 2-Methyl-5-amino benzoic acid
The desired titled compound was prepared by reducing 2-methyl-5-nitrobenzoic acid using a tin/hydrochloric acid mixture (m.p. 142-144xc2x0 C.).
Yield: 75%.
1H NMR (DMSO-d6): xcex4 12.67 (br.s, 1H), 7.23 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 3.25 (s, 2H), 2.40 (s, 3H).
Analysis for C8H9NO2: Calcd: C, 63.57; H, 6.00; N, 9.27; Found: C, 63.81; HI 6.24; N, 9.06.
B. 2-Methyl-5-hydroxybenzoic acid
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Alternate Preparation 23C, using the subtitled compound of Preparation 29A.
Yield: 65% (m.p. 136-139xc2x0 C.).
1H NMR (DMSO): xcex4 12.77 (br.s, 1H), 9.46 (br. s, 1H), 7.26 (s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 2.41 (s, 3H).
Analysis for C8H8O3: Calcd: C, 63.15; H, 5.29; Found: C, 63.27; H, 5.22.
Preparation 30
A. 5-Cyanoisoquinoline
To a cold (0xc2x0 C.) solution of 10.0 g (61.4 mmol) of 5-aminoisoquinoline in 288 mL of 1.5N hydrochloric acid, was added 15 mL of 5.2M sodium nitrite in water. After approximately 5 minutes, a cool saturated solution of sodium bicarbonate was added co she reaction mixture until the reaction solution tested negative using the iodide and starch paper test. The resultant solution was poured into a cold (0-5xc2x0 C.) biphasic mixture containing 300 ml of toluene and 150 mL of an aqueous solution containing 8.4 g (177 mmol) of sodium cyanide and 7.6 g (85 mmol) of copper cyanide. The resultant reaction mixture was warmed to room temperature, reacted for approximately 1 hour, and then diluted with a mixture of ethyl acetate and water. The resulting layers were separated, and the organic phase was dried over sodium sulfate, filtered, and then reduced to dryness under reduced pressure to provide 5.9 g of a yellow solid.
Yield: 56%.
1H NMR (CDCl3): xcex4 9.38 (s, 1H), 8.76 (d, J=5.89 Hz, 1H), 8.25 (d, J=8.29 Hz, 1H), 8.13 (d, J=8.30 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.71 (t, J=7.78 Hz, 1H);
IR (KBr): 3433, 3090, 3026, 2924, 2226 3618, 1574, 1495, 1433, 1373, 1277, 1225, 1034, 829, 766, 714.
B. 5-Carboxyisoquinoline
A solution of 6.5 g (42 mmol) of the subtitled compound of Preparation 30A in 55 mL of concentrated hydrochloric acid was heated to 155xc2x0 C. in a sealed tube for 5.5 hours and then was cooled to room temperature, and then reduced to dryness to provide a solid this solid was redissolved in 300 mL of water, and the resultant solution was adjusted to pH 6 using a dilute ammonium hydroxide solution, resulting in the precipitation of a brown solid. This solid was isolated using filtration, azeotroped with benzene, and then dried at 130xc2x0 C. under reduced pressure for approximately 3 hours to provide 5.7 g of a fine dark tan powder (m.p. 270-272xc2x0 C.).
Yield: 78%.
1H NMR (DMSO): xcex4 13.4 (br.s, 1H), 8.69 (d, 1H, J=6.00 Hz), 8.58 (d, 1H, J=4.6 Hz), 8.40 (d, 1H, J=7.37 Hz), 8.36 (d, 1H, J=8.12 Hz), 7.74 (t, 1H, J=7.76);
IR (KBr): 3460, 3014, 2930, 2851, 2777, 2405, 1912, 1711, 1622, 1574, 1493, 1427, 1375, 1264, 1211, 1152, 1044.
C. 5-Carboxyisoquinoline pentafluorophenylester
To a cold (0xc2x0 C.) solution of 1.53 g (7.39 mmol) of 1,3dicyclohexylcarbodiimide (DCC) in 60 mL of ethyl acetate, was added 1.28 g (7.39 mmol) of the subtitled compound of Preparation 30B, and 4.08 g (22.17 mmol) of pentafluorophenol in 30 mL of ethyl acetate. The resultant reaction mixture was reacted for approximately 6 hours at 0xc2x0 C. and then filtered through celite. The resultant filtrate was washed sequentially with 1N sodium hydroxide, water, and brine, and then concentrated under reduced pressure to provide a white solid. This solid was purified using column chromatography (silica; eluent of 33% ethyl acetate in hexanes) to provide 1.80 g of the desired subtitled compound. (m.p. 142-144xc2x0 C.).
Yield72%.
1H NMR (CDCl3): xcex4 9.38 (s, 1H) , 8.74 (m, 3H), 8.34 (d, J=8.1 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H);
IR (KBr) 3422, 3021, 2089, 1752, 1622, 1522, 1215, 758.
Analysis for C16H6NO2F5xc2x70.3CH2Cl2: Calcd: C, 57.30; H, 2.17; N, 4.03. Found: C, 57.40; H, 2.10; N, 4.33.
Preparation 31
5-Carboxyqinoline pentafluorophenylester
The desired subtitled compound was prepared substantially in accordance with the procedure detailed in Preparation 30C, using 0.236 g (1.36 mmol) of 5-carboxyquinoline, 0.746 g (4.05 mmol) of pentafluorophenol, and 0.571 g (2.76 mmol) of DCC in 25 mL of ethyl acetate, with the exception that the reaction mixture was allowed to react for 48 hours. The resultant crude material was purified using column chromatography to provide 0.40 g or a white solid.
Yield87%.
1H NMR (CDCl3): xcex4 9.33 (d, J=8.54 Hz, 1H) 9.03 (dd, J=4.16, 1.28 Hz, 1H), 8.63 (d, J=7.25 Hz, 1H), 8.47 (d, J=8.53 Hz, 1H); 7.87 (t, J=7.96 Hz, 1H), 7.61 (dd, J=8.76, 4.18 Hz, 1H);
IR (KBr): 3472, 2667, 2461, 1749, 1520, 1319, 1259, 1182, 1145, 1105, 1005, 947, 812.
Preparation 32
1H-indoline-4-carboxylic acid
To a cold (10xc2x0 C.) solution containing 100 mg (0.62 mmol) of indole-4-carboxylic acid in 5 mL of acetic acid, was added 390 mg (6.2 mmol) of solid sodium cyanoborohydride. The resultant mixture was reacted at room temperature for approximately 16 hours and then diluted with water. The desired compound was extracted from this solution using methylene chloride and the organic extracts were then dried over sodium sulfate and filtered. The crude material was purified using column chromatography (silica; eluent of 1% methanol in methylene chloride) to provide 12 mg of the titled compound. (m.p. 97-98xc2x0 C.).
Yield: 12%.
1H NMR (CDCl3): xcex4 7.48 (d, J=8.8 Hz, 1H), 7.34 (t, J=8.6 Hz, 1H), 6.88 (d, J=8 Hz, 1H) , 3.59 (m, 4H) .
Analysis for C9H9NO2: Calcd: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.36; H, 5.82; N, 8.42.
Preparation 33
A. 2,3-Dimethoxy-6-chlorotoluene
To a mixture of 25 g (0.16 mmol) of 1-methyl-2,3-dimethoxybenzene in 25 mL of acetic acid, was slowly added 26.4 g (0.33 mmol) of 1-chloromethylmethylether. The resultant reaction mixture was reacted overnight at 30xc2x0 C. and then diluted with cold water, resulting in the formation of a precipitate. This precipitate was purified by recrystallization from hot hexanes and then reduced to dryness under reduced pressure to provide 20.3 g of a white solid (m.p. 69-70xc2x0 C.).
Yield: 62%.
1H NMR (CDCl3): xcex4 7.01 (d, J=6.1 Hz, 1H), 6.75 (d, 4.62 (s, 2H) , 3.85 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
Analysis for C10H13O2Cl: Calcd: C, 59.93; H, 6.54; Found: C, 59.87; H, 6.43.
B. 2-Methyl-3,4-dimethoxybenzoic acid
To a mixture of 3.0 g (15 mmol) of the subtitled compound of Preparation 33A in 150 mL of water, was added 3.2 g (20 mmol) of solid potassium permangenate and 3.0 g (36 mol) of sodium carbonate. The resultant react on mixture was then heated to 80xc2x0 C. and allowed to react for approximately 24 hours. After cooling, the reaction mixture was filtered and diluted with ethyl acetate. The resultant layers were then separated and the aqueous layer was acidifed using 2N hydrochloric acid which resulted in the formation of a precipitate. This precipitate was isolated using filtration and washed with cold hexane to provide 1.7 g of a white solid (m.p. 179-180xc2x0 C.).
Yield: 58%
1H NMR (DMSO-d6): xcex4 12.49 (br.s, 1H), 7.71 (br.s, 1H), 6.99 (br.s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 2.45 (s, 3H).
Analysis for C10H12O4: Calcd: C, 61.28; H, 6.17; Found: C, 61.36; H, 6.24.
C. 2-Methyl-3,4-dihydroxybenzoic acid
To a cold (0xc2x0 C.) mixture of 250 mL (1.3 mmol) of the subtitled compound of Preparation 33B in 5 mL of methylene chloride, was added 6.4 mL of a 6.4 mmol/1.0 m solution of boron tribromide in methylene chloride. The resultant reaction mixture was reacted for approximately 90 minutes and then diluted with 25 mL of 2N hydrochloric acid. The desired compound was extracted using ethyl acetate, and the organic extracts were dried over sodium sulfate, filtered, and concentrated to provide 197 mg of a tan solid (m.p. 200-201xc2x0 C.).
Yield: 92%.
1H NMR (DMSO): xcex4 12.14 (br. s, 1H), 9.96 (br.s, 1H), 8.34 (br.s, 1H), 7.27 (d, J=7.0 Hz, 1H), 6.67 (d, J=6.7 Hz, 1H), 2.37 (s, 3H).
Analysis for C8H8O4: Calcd: C, 57.14; H, 4.80; Found: C, 57.34; H, 4.76.